Pyrimidinone carboxamide inhibitors of endothelial lipase

ABSTRACT

The present invention provides compounds of Formula (I), as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 371 of International Application No.PCT/US2013/034529 filed Mar. 29, 2013, which claims priority benefit ofU.S. provisional application Ser. No. 61/619,453, filed Apr. 3, 2012;each of which is fully incorporated by reference herein.

FIELD OF THE INVENTION

The present invention provides novel pyrimidinone carboxamide compoundsand analogues, which are endothelial lipase (EL) inhibitors,compositions containing them, and methods of using them, for example,for the treatment and/or prophylaxis of dyslipidemias and the sequelaethereof.

BACKGROUND OF THE INVENTION

Cardiovascular disease is a major health risk throughout theindustrialized world. Atherosclerosis, the most prevalent ofcardiovascular diseases, is the principal cause of heart attack, andstroke, and thereby the principal cause of death in the United States.

Atherosclerosis is a complex disease involving many cell types andmolecular factors (for a detailed review, see Ross, R., Nature,362(6423):801-809 (1993)). Results from epidemiologic studies haveclearly established an inverse relationship between levels of highdensity lipoprotein (HDL), which transports endogenous cholesterol fromtissues to the liver as well as mediating selective cholesteryl esterdelivery to steroidogenic tissues, and the risk for atherosclerosis(Gordon, D. J. et al., N. Engl. J. Med., 321(19):1311-1316 (1989)).

The metabolism of HDL is influenced by several members of thetriacylglycerol (TG) lipase family of proteins, which hydrolyzetriglycerides, phospholipids, and cholesteryl esters, generating fattyacids to facilitate intestinal absorption, energy production, orstorage. Of the TG lipases, lipoprotein lipase (LPL) influences themetabolism of HDL cholesterol by hydrolyzing triglycerides intriglyceride-rich lipoproteins, resulting in the transfer of lipids andapolipoproteins to HDL and is responsible for hydrolyzing chylomicronand very low density lipoprotein (VLDL) in muscle and adipose tissues.Hepatic lipase (HL) hydrolyzes HDL triglyceride and phospholipids,generating smaller, lipid-depleted HDL particles, and plays a role inthe uptake of HDL cholesterol (Jin, W. et al., Trends Endocrinol.Metab., 13(4):174-178 (2002); Wong, H. et al., J. Lipid Res., 43:993-999(2002)). Endothelial lipase (also known as EDL, EL, LIPG,endothelial-derived lipase, and endothelial cell-derived lipase) issynthesized in endothelial cells, a characteristic that distinguishes itfrom the other members of the family.

Recombinant endothelial lipase protein has substantial phospholipaseactivity but has been reported to have less hydrolytic activity towardtriglyceride lipids (Hirata, K. et al., J. Biol. Chem.,274(20):14170-14175 (1999); Jaye, M. et al., Nat. Genet., 21:424-428(1999)). However, endothelial lipase does exhibit triglyceride lipaseactivity ex vivo in addition to its HDL phospholipase activity, andendothelial lipase was found to hydrolyze HDL more efficiently thanother lipoproteins (McCoy, M. G. et al., J. Lipid Res., 43:921-929(2002)). Overexpression of the human endothelial lipase gene in thelivers of mice markedly reduces plasma concentrations of HDL cholesteroland its major protein apolipoprotein A-I (apoA-I) (Jaye, M. et al., Nat.Genet., 21:424-428 (1999)).

Various types of compounds have been reported to modulate the expressionof endothelial lipase, for example,3-oxo-1,3-dihydro-indazole-2-carboxamides (WO 2004/093872, US2006/0211755A1), 3-oxo-3-H-benzo[d]isoxazole-2-carboxamides (WO2004/094393, U.S. Pat. No. 7,217,727), andbenzisothiazol-3-one-2-carboxamides (WO 2004/094394, U.S. Pat. No.7,595,403) by Eli Lilly & Co.; diacylindazole derivatives (WO2007/042178, US 2008/0287448A1) and imidazopyridin-2-one derivatives (WO2007/110215, US 2009/0076068A1), and azolopyridin-3-one derivatives (WO2007/110216, US 2009/0054478A1) by Sanofi-Aventis; heterocyclicderivatives (WO 2009/123164) and keto-amide derivatives (WO 2009/133834)by Shionogi & Co., Ltd. However, because endothelial lipase is arelatively new member in the lipase gene family, a full understanding ofthe potential of endothelial lipase inhibitors to human health, as wellas the inhibitors of other lipases in general, requires more studies.

Thus, there is a clear need for new types of compounds capable ofinhibiting the activity of lipases, particularly endothelial lipase,that would constitute effective treatments to the diseases or disordersassociated with the activity of such lipases.

SUMMARY OF THE INVENTION

The present disclosure provides novel pyrimidinone carboxamide compoundsand their analogues, including stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof, which are usefulas EL inhibitors.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of dyslipidemias and the sequelae thereof.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of dyslipidemias and thesequelae thereof.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two, and other agent.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein:

ring A is independently selected from the group consisting of: C₃₋₁₀carbocycle and a 4- to 14-membered heterocycle comprising: carbon atomsand 1-4 heteroatoms selected from N, NR^(e), O, and S(O)_(p); whereineach said carbocycle and heterocycle are further substituted with 0-4R⁵;

X₁ is independently selected from the group consisting of: a bond, ahydrocarbon linker and a hydrocarbon-heteroatom linker; wherein saidhydrocarbon linker and hydrocarbon-heteroatom linker may be substitutedwith 0-2 R^(g); said hydrocarbon linker has one to six carbon atoms andmay be saturated or unsaturated; and said hydrocarbon-heteroatom linkermay be saturated or unsaturated and has zero to four carbon atoms andone group selected from O, —CO—, S, —SO—, —SO₂—, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with 0-3 R^(a), C₂₋₆ alkenylsubstituted with 0-3 R^(a),

and —(CH₂)_(n)—(C₃₋₁₀ carbocycle substituted with 0-3 R^(c));

R² is independently selected from the group consisting of: OR⁶ and NHR⁷;

R⁴ is independently selected from the group consisting of: H, ═O,halogen, C₁₋₆ alkyl substituted with 0-1 OH, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, NH₂, N(C₁₋₄ alkyl)₂, and a ringmoiety substituted with 0-2 R^(h) and selected from: C₃₋₁₀ carbocycleand a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S(O)_(p);

R⁵ is, independently at each occurrence, selected from the groupconsisting of: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 OH, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NH₂, NO₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂(C₁₋₄ alkyl),CO(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), and CON(C₁₋₄ alkyl)₂;

R⁶ is independently selected from the group consisting of: H and C₁₋₆alkyl substituted with 0-1 R⁸;

R⁷ is independently selected from the group consisting of: H, COCF₃,C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with 0-1 R^(a),—(CHR^(f))_(n)—(C₃₋₁₀ carbocycle substituted with 0-3 R^(b)), and—(CHR^(f))_(n)-(5- to 10-membered heterocycle comprising: carbon atomsand 1-4 heteroatoms selected from N, NR^(e), O, and S(O)_(p)); andwherein said heterocycle is substituted with 0-3 R^(c);

R⁸ is independently selected from the group consisting of: CO₂H and OH;

R^(a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, NH₂, NO₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, CO₂H,CO₂(C₁₋₄ alkyl), NHCO(C₁₋₄ alkyl substituted with 0-1 NH₂), N(C₁₋₄alkyl)CO(C₁₋₄ alkyl), NHCO₂(C₁₋₄ alkyl), CONHSO₂(C₁₋₄ alkyl), SO₂(C₁₋₄alkyl), CONH₂, CONH(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), N(C₁₋₄alkyl)SO₂(C₁₋₄ alkyl), phenoxy, and —CONH(phenylcyclohexyl);

R^(b) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl substituted with 0-1 OH, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NH₂, NO₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄alkyl)₂, NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), N(C₁₋₄ alkyl)SO₂(C₁₋₄alkyl), SO₂(C₁₋₄ alkyl), SO₂NH₂, phenyl, benzyl, and phenoxy;

R^(c) is, independently at each occurrence, selected from the groupconsisting of: ═O and R^(b);

R^(d) is, independently at each occurrence, selected from the groupconsisting of: CONH₂, C₁₋₄ alkyl, —(CH₂)₂O(CH₂)₂O(C₁₋₄ alkyl),C₃₋₆-carbocycle substituted with 0-2 R^(h), morpholin-1-yl, 1-C₁₋₄alkyl-piperazin-4-yl, 1-CBz-piperazin-4-yl, pyridyl, indol-3-yl, andbenzothiazol-2-yl;

R^(e) is, independently at each occurrence, selected from the groupconsisting of: H, C₁₋₄ alkyl, CO(C₁₋₄ alkyl), CO₂(C₁₋₄ alkyl),CO₂(benzyl), CONH(C₁₋₄ alkyl), CONH(phenyl substituted with 0-2halogens), SO₂(C₁₋₄ alkyl), and —(CH₂)_(n)R^(d);

R^(f) is, independently at each occurrence, selected from the groupconsisting of: H and C₁₋₄ alkyl;

R^(g) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, CO₂(C₁₋₄ alkyl), C₃₋₆ cycloalkyl, and phenyl;

R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, —(CH₂)₂O(C₁₋₄ alkyl), CF₃, NO₂, CONH₂, OBn, quinolinyl,1-C₁₋₄ alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-C₁₋₄alkyl-3-CF₃-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, N(C₁₋₄alkyl)₂, CONH₂, and NHCO(C₁₋₄ alkyl));

n is, independently at each occurrence, selected from 0, 1, 2, 3, and 4;and

p is, independently at each occurrence, selected from 0, 1, and 2.

In a second aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the first aspect, wherein:

ring A is independently selected from the group consisting of: C₃₋₁₀carbocycle and a 4- to 13-membered heterocycle comprising: carbon atomsand 1-4 heteroatoms selected from N, NR^(e), O, and S(O)_(p); whereineach said carbocycle and heterocycle is substituted with 0-3 R⁵;

X₁ is independently selected from the group consisting of: a bond, ahydrocarbon linker and a hydrocarbon-heteroatom linker; wherein saidhydrocarbon linker and hydrocarbon-heteroatom linker may be substitutedwith 0-1 R^(g); said hydrocarbon linker may be saturated or unsaturatedand has one to five carbon atoms; and said hydrocarbon-heteroatom linkermay be saturated or unsaturated and has zero to four carbon atoms andone group selected from O, —CO—, S, —SO—, —SO₂—, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆haloalkyl,

and —(CH₂)_(n)-(phenyl substituted with 0-3 R^(c)C);

R² is independently selected from the group consisting of: OR⁶ and NHR⁷;

R⁴ is independently selected from the group consisting of: H, C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and a ringmoiety substituted with 0-2 R^(h) and selected from: C₃₋₁₀ carbocycleand a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S(O)_(p);

R⁵ is, independently at each occurrence, selected from the groupconsisting of: OH, halogen, C₁₋₄ alkyl substituted with 0-1 OH, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, CO₂(C₁₋₄ alkyl),—CH₂CO₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), and N(C₁₋₄ alkyl)₂; and

R⁶ is independently selected from the group consisting of: H and C₁₋₄alkyl substituted with 0-1 CO₂H.

In a third aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the first or second aspect,wherein:

ring A is independently selected from the group consisting of: c,

wherein each moiety is substituted with 0-2 R⁵; and

X₁ is independently selected from the group consisting of: a bond, ahydrocarbon linker and a hydrocarbon-heteroatom linker; wherein saidhydrocarbon linker and hydrocarbon-heteroatom linker may be substitutedwith 0-1 R^(g); said hydrocarbon linker may be saturated or unsaturatedand has one to four carbon atoms; and said hydrocarbon-heteroatom linkermay be saturated or unsaturated and has zero to three carbon atoms andone group selected from O, —CO—, S, —SO—, —SO₂—, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —OCONH—, —NHCONH—, and —SO₂NH—.

In a fourth aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of any of the above aspects,wherein:

ring A is independently selected from the group consisting of:

wherein each moiety is substituted with 0-2 R⁵;

X₁ is independently selected from the group consisting of: a bond, O,CO, straight or branched C₁₋₃ alkylene, —O—C₁₋₃ alkylene-, —C₁₋₃alkylene-O—, NH, —SO₂—, —C₁₋₃ alkylene-NH—, —NHCO—, —CONH—, —CH₂NHCO—,—CH₂CONH—, —OCONH—, —CH₂OCONH—, —NHCONH—, and —SO₂NH—;

alternatively,

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(CH₂)₂OH, —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₁₋₃Ph, 3-halo-4-halo-phenyl, 3-halo-5-CF₃-phenyl, and

R² is independently selected from the group consisting of: OH and NHR⁷;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, NO₂, CO₂(C₁₋₄ alkyl), —CH₂CO₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄alkyl), and N(C₁₋₄ alkyl)₂;

R⁷ is independently selected from the group consisting of: H, C₁₋₆haloalkyl, COCF₃, —(CH₂)₂O(C₁₋₄ alkyl), C₁₋₆ alkyl substituted with 0-1OH, —(CHR^(f))_(n)—(C₃₋₆ cycloalkyl substituted with 0-1 OH),—(CHR^(f))_(n)-(phenyl substituted with 0-2 R^(b)), 1-tetralinyl,1-indanyl, tetrahydronaphthalenyl, 1-Bn-pyrrolidin-3-yl,—(CH₂)_(n)-(piperidin-1-yl), 1-C₁₋₄ alkyl-piperidiny-4-yl, 1-CO₂(C₁₋₄alkyl)-piperidiny-4-yl, 1-(4-halo-phenyl)-piperidiny-4-yl,—(CH₂)_(n)(morpholin-4-yl), —(CH₂)_(n)-imidazolyl, —(CH₂)_(n)-pyridyl,

R^(b) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl substituted with 0-1 OH, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NH₂, NO₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄alkyl)₂, NHCO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and SO₂NH₂;

R^(f) is, independently at each occurrence, selected from the groupconsisting of: H and methyl;

R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, —(CH₂)₂O(C₁₋₄ alkyl), CF₃, NO₂, CONH₂, OBn, quinolinyl,1-C₁₋₄ alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-C₁₋₄alkyl-3-CF₃-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, N(C₁₋₄alkyl)₂, CONH₂, and NHCO(C₁₋₄ alkyl)); and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In a fifth aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of any of the above aspects,wherein:

ring A is independently selected from the group consisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, —SO₂—, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CONH—,—CH₂NHCO—, —CH₂CONH—, —OCONH—, —CH₂OCONH—, —NHCONH—, and —SO₂NH—;

alternatively,

R¹ is independently selected from the group consisting of: H, C₁₋₄alkyl, —(CH₂)₂OH, —CH₂CO₂H, CH₂CF₃, CH₂CH₂CF₃, —(CH₂)₁₋₃Ph, and

R³ is independently selected from the group consisting of: H, C₁₋₄alkyl, CH₂CF₃, —(CH₂)₁₋₃Ph, 3-halo-4-halo-phenyl, 3-halo-5-CF₃-phenyl,and benzyl;

R⁴ is independently selected from the group consisting of: H, C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, pyrazolyl,oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, benzothiazolyl, and1H-pyrazolo[3,4-d]pyrimidinyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO₂(C₁₋₄ alkyl), andNH₂;

R⁷ is independently selected from the group consisting of: H, C₁₋₆ alkylsubstituted with 0-1 OH, C₁₋₆ haloalkyl, —(CH₂)₂O(C₁₋₄ alkyl), C₃₋₆cycloalkyl, —CH(CH₃)(cyclohexyl), —(CH₂)₁₋₃-(phenyl substituted with 0-2R^(b)), tetrahydronaphthalenyl, 1-Bn-pyrrolidin-3-yl, 1-C₁₋₄alkyl-piperidin-4-yl, —(CH₂)₂(piperidin-1-yl), —(CH₂)₂(morpholin-4-yl),—(CH₂)₃(morpholin-4-yl), —(CH₂)₂(1H-imidazol-4-yl),—(CH₂)₃(imidazol-1-yl), —CH₂-pyridyl, and

and

R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —(CH₂)₂O(C₁₋₄alkyl), CF₃, NO₂, CONH₂, OBn, quinolinyl, 1-C₁₋₄ alkyl-pyrazolyl,1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-C₁₋₄ alkyl-3-CF₃-pyrazolyl,1-Ph-5-C₁₋₄ alkyl-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, N(C₁₋₄ alkyl)₂, CONH₂, andNHCO(C₁₋₄ alkyl)).

In a sixth aspect, the present invention includes a compound of Formula(I), wherein R² is NHR⁷, further characterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of any of the above aspects.

In a seventh aspect, the present invention includes a compound ofFormula (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

ring A is independently selected from the group consisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, SO₂, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CONH—,—CH₂NHCO—, —CH₂CONH—, —CH₂OCONH—, and —SO₂NH—;

alternatively,

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₄ alkyl, CH₂CF₃, and benzyl;

R⁴ is independently selected from the group consisting of: H, C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, pyrazolyl,oxadiazolyl, triazolyl, pyridyl, benzothiazolyl, and1H-pyrazolo[3,4-d]pyrimidinyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and CO₂(C₁₋₄ alkyl);

R⁷ is independently selected from the group consisting of: H, C₁₋₆alkyl, CH₂CF₃, —(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)₂OH, —CH(CH₃)CH₂OH,—CH₂C(CH₃)₂OH, C₃₋₆ cycloalkyl, —CH(CH₃)(cyclohexyl), —(CH₂)₁₋₃-(phenylsubstituted with 0-2 R^(b)), tetrahydronaphthalenyl,1-Bn-pyrrolidin-3-yl, 1-C₁₋₄ alkyl-piperidin-4-yl,—(CH₂)₂(piperidin-1-yl), —(CH₂)₂(morpholin-4-yl),—(CH₂)₃(morpholin-4-yl), —(CH₂)₂(1H-imidazol-4-yl),—(CH₂)₃(imidazol-1-yl), —CH₂(pyrid-3-yl), —CH₂(pyrid-4-yl), and

R^(b) is, independently at each occurrence, selected from the groupconsisting of: halogen, CH₂OH, CF₃, and SO₂NH₂;

R^(d) is, independently at each occurrence, selected from the groupconsisting of: C₁₋₄ alkyl and phenyl substituted with 0-2 R^(h); and

R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CONH₂,OBn, quinolinyl, 1-C₁₋₄ alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄alkyl))-pyrazolyl, 1-C₁₋₄ alkyl-3-CF₃-pyrazolyl, 1-Ph-5-C₁₋₄alkyl-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, N(C₁₋₄ alkyl)₂, CONH₂, andNHCO(C₁₋₄ alkyl)).

In an eighth aspect, the present invention includes a compound ofFormula (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

ring A is independently selected from the group consisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, SO₂, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CONH—,—CH₂NHCO—, —CH₂OCONH—, and —SO₂NH—;

R⁴ is independently selected from the group consisting of: H, C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, tetrahydronaphthalenyl, pyrazolyl, oxadiazolyl,triazolyl, pyridyl, benzothiazolyl, and 1H-pyrazolo[3,4-d]pyrimidinyl;

R⁷ is independently selected from the group consisting of: H,—(CH₂)₂O(C₁₋₄ alkyl), —CH₂C(CH₃)₂OH, cyclopentyl, 4-halo-benzyl,2-CH₂OH-benzyl, 3-CF₃-benzyl, 2-halo-phenethyl, 4-halo-phenethyl,—(CH₂)₃Ph, 1-Bn-pyrrolidin-3-yl, —(CH₂)₂(piperidin-1-yl),—(CH₂)₂(morpholin-4-yl), —(CH₂)₃(morpholin-4-yl),—(CH₂)₂(1H-imidazol-4-yl), and —CH₂(pyrid-3-yl); and

R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OBn,quinolinyl, 1-C₁₋₄ alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl,1-Ph-pyrazolyl, 1-C₁₋₄ alkyl-3-CF₃-pyrazolyl, 1-Ph-5-C₁₋₄alkyl-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl, 1,2,5-triC₁₋₄alkyl-pyrazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl), and—(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,CONH₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and N(C₁₋₄ alkyl)₂).

In a ninth aspect, the present invention includes a compound of Formula(II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of any of the above aspectswherein:

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₄ alkyl and benzyl;

is independently selected from the group consisting of:

R⁷ is independently selected from the group consisting of: H,—(CH₂)₂O(C₁₋₄ alkyl), —CH₂C(CH₃)₂OH, 4-halo-benzyl, 4-halo-phenethyl,—(CH₂)₂(morpholin-4-yl), and —(CH₂)₃(morpholin-4-yl).

In a tenth aspect, the present invention includes a compound of Formula(I), wherein R² is OH, further characterized by Formula (III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of any of the first to fifth aspect.

In an eleventh aspect, the present invention includes a compound ofFormula (III), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst to fifth or tenth aspect, wherein:

R¹ is independently selected from the group consisting of: H, C₁₋₄alkyl, —(CH₂)₂OH, —CH₂CO₂H, CH₂CF₃, CH₂CH₂CF₃, —(CH₂)₁₋₃-Ph,

R³ is independently selected from the group consisting of: H, C₁₋₄ alkyland benzyl; and

is independently selected from the group consisting of:

In a twelfth aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the twelfthaspect.

In another embodiment, the compounds of the present invention have ELIC₅₀ values ≦10 μM.

In another embodiment, the compounds of the present invention have ELIC₅₀ values ≦5 μM.

In another embodiment, the compounds of the present invention have ELIC₅₀ values ≦1 μM.

In another embodiment, the compounds of the present invention have ELIC₅₀ values ≦0.5 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition as defined above further comprising additional therapeuticagent(s).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of dyslipidemias and the sequelae thereofcomprising administering to a patient in need of such treatment and/orprophylaxis a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity ofendothelial lipase that can be prevented, modulated, or treatedaccording to the present invention include, but are not limited to,atherosclerosis, coronary heart disease, coronary artery disease,coronary vascular disease, cerebrovascular disorders, Alzheimer'sdisease, venous thrombosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia.

In one embodiment, the present invention provides a method for thetreatment and/or prophylaxis of atherosclerosis, coronary heart disease,cerebrovascular disorders and dyslipidemia, comprising administering toa patient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of dyslipidemias and the sequelae thereof.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of dyslipidemias and the sequelaethereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of dyslipidemias and the sequelae thereof,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of a first and second therapeutic agent, wherein thefirst therapeutic agent is a compound of the present invention.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of dyslipidemias and the sequelae thereof.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-thrombotic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, treatments for heartfailure, treatments for peripheral arterial disease, treatment formalignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating atherosclerosis: anti-hyperlipidemicagents, plasma HDL-raising agents, anti-hypercholesterolemic agents,cholesterol biosynthesis inhibitors (such as HMG CoA reductaseinhibitors), acyl-coenzyme A:cholesterol acyltransferase (ACAT)inhibitors, LXR agonist, probucol, raloxifene, nicotinic acid,niacinamide, cholesterol absorption inhibitors, bile acid sequestrants(such as anion exchange resins, or quaternary amines (e.g.,cholestyramine or colestipol)), low density lipoprotein receptorinducers, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidant vitamins, β-blockers,anti-diabetes agents, angiotensin II antagonists, angiotensin convertingenzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptorantagonists, aspirin or fibric acid derivatives.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating cholesterol biosynthesis inhibitor,particularly an HMG-CoA reductase inhibitor. Examples of suitableHMG-CoA reductase inhibitors include, but are not limited to,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, andrivastatin.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C≡C doublebonds, C≡N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle,” “carbocyclyl,” or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, cyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl,” “C₆₋₁₀ aryl,” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, selected from—OH, —OCH₃, —Cl, —F, —Br, —I, —CN, —NO₂, —NH₂, —N(CH₃)H, —N(CH₃)₂, —CF₃,—OCF₃, —C(O)CH₃, —SCH₃, —S(O)CH₃, —S(O)₂CH₃, —CH₃, —CH₂CH₃, —CO₂H, and—CO₂CH₃.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle,” “heterocyclyl,” or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C≡C, C≡N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As a person of ordinary skill in the art would be able to understand, aketone (—CH—C═O) group in a molecule may tautomerize to its enol form(—C≡C—OH), as shown in the following equation, wherein R═R⁴—X₁-A:

Likewise, an imine (—CH—C≡NHR) group in a molecule may tautomerize toits enamine form (—C≡C—NHR), as shown in the following equation forillustration purpose:

Various tautomerized forms may occur when both R¹ and R³ are hydrogen,when R¹═H and R³≠H, or when R¹≠H and R³═H. For example, some possibletautomerized forms are shown for illustration purpose for the compoundswhen R² is OH and both R¹ and R³ are hydrogen.

For example, some possible tautomerized forms are shown for illustrationpurpose for the compounds when R² is NH₂ and both R¹ and R³ arehydrogen.

Thus, this disclosure is intended to cover all possible tautomers evenwhen a structure depicts only one of them.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of Formula (I), Formula (II), or Formula (III)may have prodrug forms. Any compound that will be converted in vivo toprovide the bioactive agent (i.e., a compound of Formula (I), Formula(II) or Formula (III)) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,”Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield Formula (I), Formula (II), Formula (III), or Formula (IV)compounds per se. Such prodrugs are preferably administered orally sincehydrolysis in many instances occurs principally under the influence ofthe digestive enzymes. Parenteral administration may be used where theester per se is active, or in those instances where hydrolysis occurs inthe blood. Examples of physiologically hydrolyzable esters of compoundsof Formula (I), Formula (II), Formula (III), or Formula (IV) include C₁to C₆ alkyl, C₁ to C₆ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆ alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl), C₁ to C₆ alkoxycarbonyloxy-C₁to C₆ alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more, preferably one to three, solvent molecules areincorporated in the crystal lattice of the crystalline solid. Thesolvent molecules in the solvate may be present in a regular arrangementand/or a non-ordered arrangement. The solvate may comprise either astoichiometric or nonstoichiometric amount of the solvent molecules.“Solvate” encompasses both solution-phase and isolable solvates.Exemplary solvates include, but are not limited to, hydrates,ethanolates, methanolates, and isopropanolates. Methods of solvation aregenerally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar, “nM”for nanomolar, “mol” for mole or moles, “mmol” for millimole ormillimoles, “min” for minute or minutes, “h” for hour or hours, “rt” forroom temperature, “RT” for retention time, “atm” for atmosphere, “psi”for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd”for saturated, “MW” for molecular weight, “mp” for melting point, “MS”or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Cbz carbobenzyloxy-   CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CDCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDTA ethylenediaminetetraacetic acid-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   HCl hydrochloric acid-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl_(2 [)1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   PMB p-methoxybenzyl-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   PS-Pd(Ph₃)₄ tetrakis(triphenylphosphine)palladium (0) on polystyrene    support-   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAF tetra-n-butylammonium fluoride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being affected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

A particularly useful compendium of synthetic methods which may beapplicable to the preparation of compounds of the present invention maybe found in Larock, R. C., Comprehensive Organic Transformations, VCH,New York (1989). Preferred methods include, but are not limited to,those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Wiley and Sons (1991)).

Schemes 1-21 describe synthetic routes for making intermediates andcompounds of the present invention. Schemes 1-3 describe preparation ofcompounds of the present invention from key intermediates 2, 4 or 5.Schemes 4-6 illustrate several preparations for thehydroxypyrimidinedione esters from commercially available startingmaterials. Scheme 7 describes the preparation of aminopyrimidine dioneester 17 from commercially available starting materials. Schemes 8, 9and 21 illustrate the synthesis of N−1 substituted or N−3 substitutedhydroxypyrimidinedione analogs in the present invention. Schemes 10 and11 exemplify the preparations of compounds of the present inventionwherein R² is either an NH₂ group or a NHR group. Scheme 12 illustratesthe selective N-arylation or N-alkenylation of the NH group at the 3position of the pyrimidine dione core. Scheme 13 describes the generalamine intermediates for the preparation of compounds of the presentinvention. Schemes 14-19 exemplify the preparation of examples of someof these amine intermediates. Scheme 20 describes the conversion of5-amino to 5-hydroxy group under acidic conditions.

Scheme 1 describes a preparation of compounds of Formula (I) of thepresent invention from the key intermediate acid 2. The amineintermediates 3 (R⁴—X₁-A-L-NH₂) or their HCl or TFA salts are eithercommercially available or can be readily prepared from commerciallyavailable materials by methods known to one skilled in the art oforganic synthesis. Reaction of amine 3 with acid 2 can occur understandard amide coupling conditions at temperatures between 0° C. and100° C. in a variety of solvents such as DMF or dichloromethane. Theprotocols include, but are not limited to, formation of the acidchloride of 2 using either oxalyl chloride and catalytic DMF in thepresence of a suitable solvent such as dichloromethane or thionylchloride, followed by addition of amine 3 in the presence of a base suchas TEA, DIPEA or N-methylmorpholine, or formation of the active ester ofintermediate 2 using EDC, HOBt, PyBOP and a base, such as TEA, DIPEA orN-methylmorpholine, in the presence of amine 3.

Alternatively, compounds of Formula (I) of the present invention can beprepared by displacement of the methyl ester 4 with the amines 3 inpolar solvents such as ethanol, DMF, or neat at elevated temperatures orunder microwave irradiation as shown in Scheme 2.

Compounds of Formula (I) wherein R²═OH can be made by the generalmethods described in Schemes 1 and 2. Alternatively, R² can be hydroxylgroup protected as shown in intermediate 5 (Scheme 3), wherein theprotecting group can be methyl, benzyl, allyl, or silyl-based groups.Amide formation between the ester or acid 5 and the amine 3, followed bydeprotection to free the hydroxyl group in intermediate 6 can afford thecompounds of Formula (I) (wherein R²═OH). When the protecting group onthe hydroxyl group is methyl, ethyl, isopropyl, or benzyl, deprotectioncan occur with BBr₃, BCl₃, BBr₃.SMe, BCl₃.SMe AlCl₃, or BCl₃/TBAI attemperatures between −78° C. and refluxing in a solvent such as CH₂Cl₂.When heating is required, the reaction can also occur under microwaveirradiation to shorten the reaction time. When the protecting group onthe hydroxyl group is a benzyl group, debenzylation can also occur byhydrogenation (such as Pd/C, H₂) or by heating in TFA under microwaveirradiation with or without a solvent, such as CH₂Cl₂, or by using AlCl₃in CH₂Cl₂ in a variety of solvent such as methanol or EtOAc.

Scheme 4 describes the preparation of 5-hydroxy pyrimidinone carboxylicacid intermediates 7 (R²═OH) by ring construction. An oxalic aciddiester is condensed with glycolate using lithiumbis(trimethylsilyl)amide or a similar base, followed by reacting with2-methyl-2-thiopseudourea sulfate in one-pot to give the pyrimidinoneintermediate 8 (US 2005/0261322A1 and Dreher, S. D. et al., TetrahedronLetters, 45(31):6023-6025 (2004)). The intermediate methylsulfide 8 canthen be oxidized to sulfone 9 by using standard oxidation reagents, suchas mCPBA, hydrogen peroxide, or OXONE®. The resulting pyrimidinonesulfone 9 is stirred in the presence of an aqueous base, such as NaOH,KOH in solvent, such as dioxanes, to afford intermediate 7.

Alternatively, 2-oxo or 2-thioxo-tetrahydropyrimidinones 10 can besynthesized from the condensation of dihydroxyfumarate derivatives 11with alkyl/aryl carbamimidates or alkyl/aryl carbamimidothioates 12,followed by deprotection to remove the alkyl or aryl groups onintermediate 13 and tautomerization as shown in Scheme 5.

Alternatively, the pyrimidinone 13 can be synthesized as shown in Scheme6 via Michael addition of N-hydroxy amidine 15 to acetylynic diesters16, followed by thermal Claisen rearrangement and amide condensation(Culbertson, T. P., J. Heterocycl. Chem., 16:1423-1424 (1979)).

Similarly the corresponding 5-aminopyrimidinone 17 (R=Me or H) can besynthesized as shown in Scheme 7 using an aza-Claisen rearrangement,starting with (E)-methyl carbamohydrazonothioate 18.

The thioether 8 shown in Scheme 8 is an intermediate for the preparationof N−1 or N−3 substituted 5-hydroxypyrimidinediones of Formula (I) ofthe present invention. Intermediate 8 can be N−1 alkylated with alkylhalides or benzyl halides (X═Br or Cl) in the presence of an inorganicor organic base (such as K₂CO₃, Cs₂CO₃, Et₃N, NaH, LiH). Alternatively,pyrimidinone 8 can be N−1 arylated using Ullmann-Goldberg reaction (CuI,base heating), or Buchwald modified Ullmann reaction (CuI, ligand, base,heating) or Pd C≡N cross-coupling reaction (Pd(OAc)₂, or other Pd(0)catalysts, base, ligand, heating) with aryl halides or copper-mediatedcross-coupling reaction (Cu(OAc)₂, base (such as Et₃N, pyridine) witharyl boronic acids. Alternatively, pyrimidinone 8 can be alkylated byMitsunobu protocol with a suitable alcohol. For example, alkylation ofpyrimidinone 8 with alkyl halides or benzyl halides in the presence ofan inorganic or organic base (such as K₂CO₃, Cs₂CO₃, Et₃N, NaH, LiH) canafford both the N−1 alkylated pyrimidinone intermediate 19 and theO-alkylated intermediate 20. Following similar sequences as shown inScheme 4, the N−1 substituted acid 21 can be obtained. Formation of theamide of intermediate 21 followed by deprotection can provide N−1substituted compound 22. Alternatively, O-alkylated pyrimidine 20 can beoxidized to the corresponding sulfone then hydrolyzed to pyrimidinone23. Intermediate 23 can be further alkylated at the N−3 positionfollowed by removal of the R¹ and PG groups to give the N−3 substitutedester 25. Hydrolysis of the ester in intermediate 25 followed by amideformation and then deprotection can provide the corresponding N−3substituted compound 26.

Similarly, the N−1 substituted compound 22 and the N−3 substitutedcompound 26 can also be prepared using the synthetic route shown inScheme 9.

Scheme 10 illustrates one preparation of compounds of Formula (I) of thepresent invention wherein R² is either a NH₂ (Compound 33) or NHR group(Compound 34). The route involves the condensation of 2-oxosuccinicdiesters 35 with amidines 12. The resulting 5-H pyrimidinone analog 36can be oxidized to intermediate 5-H pyrimidine dione 37 which can thenbe brominated by standard bromination reagents, such as bromine or NBS.The 5-amino group can be introduced by displacement of the bromide 38with p-methoxybenzyl amine in polar solvents such as ethanol, ethyleneglycol, dioxanes, under microwave irradiation, followed by removal ofPMB group with TFA. Compounds of Formula (I) of the present inventionwhere in R² is NHR (Compound 34) can be prepared by displacement of thebromide 38 with amines NH₂R in polar solvents such as ethanol, DMF,ethylene glycol or neat at elevated temperatures or under microwaveirradiation as shown in Scheme 10. Alternatively, compound 34 can beprepared from the bromide 38 by using Ullmann coupling reactions (basesuch as K₂CO₃, Cu(I) catalyst such as CuCl or CuI, with or withoutligand, solvent such as DMSO, DMF or ethylene glycol) or by using Pdcatalyzed Buchwald-Hartwig reaction with suitable amines.

Scheme 11 depicts an alternate synthesis of 5-aminopyrimidinone 33 from2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 37 by nitrosationwith sodium nitrite in acetic acid followed by reduction of the nitrosogroup in 39 with sodium dithionite. (Elzein, E. et al., J. Med. Chem.,51:2267-2278 (2008); Zhang, Y. J., Tetrahedron Letters, 47(5):775-778(2006)). Alternatively 5-aminopyrimidinone can be synthesized from2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide by nitration usingstandard nitration condition followed by reduction of nitro group in 40to the amino group with reducing agents, such as Fe/HCl, orhydrogenation condition, such as Pd/C/hydrogen (Baraldi, P. G. et al.,J. Med. Chem., 45(17):3630-3638 (2002); Zajac, M. A. et al., SyntheticCommunications, 33(19):3291-3297 (2003)).

Scheme 12 illustrates one preparation of N−3 substituted analogs 41 fromintermediate 42. Regioselective arylation or alkenlation of the N−3 NHgroup of intermediate 41 can be realized by using modified Chan-LamCu-prompted C≡N cross-coupling reaction with R³—B(OH)₂ and related boronreagents as described in Yang Yue et al., Eur. J. Org. Chem., 5154-5157(2005); Lan Tao et al., Helvetica Chimica Acta 91(6):1008-1014 (2008).

Scheme 13 illustrates examples of amine intermediates NH₂-A-X₁—R⁴(compound 3, Scheme 1) that can be used to prepare compounds of thepresent invention. These intermediates are either commercially availableor can be prepared using methods, examples of which are shown in Schemes14-19, known to those skilled in the art of organic synthesis.

Scheme 14 outlines one possible preparation of amine intermediates 43,wherein L in Formula (I) is a cycloalkyl ring. Reductive amination ofthe cyclic ketone 44 with diphenylmethanamine followed by separation ofthe cis- and trans-isomers using silica gel chromatography andsubsequent hydrogenation provided the desired cis or trans amines 43.Alternatively, amine 43 can be obtained from reduction of the oximeintermediate 44. Alternatively, the carbonyl in ketone 44 can be reducedto OH followed by activation and displacement with NaN₃ and reduction ofthe corresponding azide 47.

The cyclohexanone starting material 44 is either commercially availableor can be readily prepared from commercially available materials bymethods known to one skilled in the art of organic synthesis. Forexample, in Scheme 15, transformation of ketal 48 to vinyl OTf followedby C≡C formation of R⁴—B(OH)₂ with the vinyl triflate can afford thecorresponding vinyl intermediate 49. Hydrogenation of intermediate 49followed by deprotection of the ketal group under acidic condition cangive the desired ketone 44. Alternatively, treatment of the ketalintermediate 48 with R⁴—Li (generated by nBuLi with bromo or iodo R⁴species) can give the corresponding alcohol 50, which can be eliminatedto give the vinyl intermediate and reduced and the acetal hydrolyzed toprovide cyclohexane 44. Alternatively, alcohol 50 can be directlyreduced with triethylsilane followed by deprotection of the ketal groupof intermediate 51 under acidic condition can provide the desired ketoneintermediate 44.

Scheme 16 illustrates bicyclic amines 52A and 52B (R⁴—X₁-A-NH₂) whereinR⁴— X₁-A is an indane or a tetralin or a6,7,8,9-tetrahydro-5H-benzo[7]annulene ring. The ketone startingmaterial 53 is either commercially available or can be readily preparedfrom commercially available materials by methods known to one skilled inthe art of organic synthesis. For example, the ketone 53 can be preparedby Friedel-Crafts reaction of acid 54 or by intramolecular cyclizationof halide 55 using nBuLi. The individual diastereomers can be obtainedby using Ellman's t-butylsulfinamide methodology (Ellman, J. A., J. Org.Chem., 72(2):626-629 (2007): reduction of sulfinamide 56 with eitherNaBH₄ or L-selectride at low temperature (for examples, −40 to −50° C.)in THF to give the diastereomers 57A and 57B after silica gel columnchromatography or SFC separation. Intermediates 57A and 57B werehydrolyzed to give the desired enantiopure amines 52A and 52B,respectively.

The 1,3-cycloalkylamines 58, such as 1,3-cyclohexylamines or1,3-cyclopentylamines, can be readily prepared by using methods known toone skilled in the art of organic synthesis (Scheme 17). For example,transformation of diketone 59 to the corresponding vinyl halide or vinyltriflate intermediate 60, followed by C≡C bond formation with R⁴—B(OH)₂in the presence of a palladium source, such as Pd(OAc)₂, Pd₂(dba)₃,Pd(PPh₃)₄, and a base such as Na₂CO₃, K₃PO₄, in solvents such as tolueneand water, can afford intermediate 61. Reductive amination of 61followed by hydrogenation can give the racemic 1,3-cycloalkylamines 58.Alternatively, treatment of the ketal intermediate 62 with R⁴—Li(generated by nBuLi with bromo or iodo R⁴ species) can give thecorresponding alcohol, which can be eliminated to give the vinylintermediate 61.

The 1,3-cycloalkylnone can be synthesized directly from 1,4-Michaeladdition of α,β-unsaturated carbonyl compounds with organoborons (Scheme18). Arylboronic acids react with 64 in the presence of a base and acatalytic amount of a palladium(0) complex with chloroform, affordingthe corresponding addition products 63 in good yield (Yamamoto et al.,J. Organometallic Chemistry, 694:1325-1332 (2009)).

Asymmetric Michael addition of arylboronic acids to α,β-unsaturatedcarbonyl compounds utilizing in situ generated chiralrhodium-binap-based catalyst can give enantiopure cycloketones 65 inhigh levels of enantioselectivity (Kirill Lukin, J. Org. Chem.,74:929-931 (2009)). The individual diastereomers can be obtained byusing Ellman's t-butylsulfinamide methodology, followed by silica gelcolumn chromatography or SFC separation, as described in Schemes 16 and17. Alternatively, the separation of optical isomers of 1,3-alkylanolscan be achieved by a lipase-catalyzed transesterification as indicatedin Scheme 19 (Makoto Shimizu et al., Tetrahedron, 8729-8736 (2002);Fensholdt, J. et al., WO 2009/065406). The enantiopure alcohols then canbe transformed to the corresponding amines by using the methodsdescribed in Scheme 14.

Scheme 20 illustrates that 5-aminoorotic amides can be transformed to5-hydroxyorotic amides under acidic condition (such as 1 N HCl) withcompatible solvents, such as dioxane, ethanol, etc. at reflux, and withor without a catalyst, such as TiCl₄.

Scheme 21 describes the preparation of N−1 substituted5-hydroxypyrimidinediones of Formula (I) of the present invention.Compound 13 (when W═O) can be N-alkylated and O-alkylated according tomethods similar to Scheme 8. When NaH or LiH is used as the base withaprotic solvents, O-alkylation can be reduced to afford more favorableN-alkylated products (Gambacorta, A. et al., Tetrahedron, 62:6848-6854(2006)). After removal of the protective group in compound, theresulting carboxylic acid 73 was then reacted with amines under standardamide coupling conditions to give 74, which is deprotected to give theN−1 alkylated 75. Alternatively, compound 13 can be selectivelydeprotected to give carboxylic acid 76. Amide formation of 76 withamines followed by N−1 alkylation and then deprotection can provide theN−1 substituted compound 75.

General Methods

The following methods were used in the exemplified Examples, exceptwhere noted otherwise.

Products were analyzed by reverse phase analytical HPLC carried out on aShimadzu Analytical HPLC system running Discovery VP software usingMethod A: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm), or Method B: PHENOMENEX® Luna C18 column (4.6×50 mm) elutedat 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10%acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile,0.1% TFA, UV 220 nm) or Method C: PHENOMENEX® Luna C18 column (4.6×50 mmor 4.6×75 mm) eluted at 4 mL/min with a 2, 4 or 8 min gradient from 100%A to 100% B (A: 10% methanol, 89.9% water, 0.1% H₃PO₄; B: 10% water,89.9% methanol, 0.1% H₃PO₄, UV 220 nm) or Method D: PHENOMENEX® Luna C18column (4.6×50 mm or 4.6×75 mm) eluted at 4 mL/min with a 2, 4 or 8 mingradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1%NH₄OAc; B: 10% water, 89.9% methanol, 0.1% NH₄OAc, UV 220 nm).

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutedwith gradients of hexanes and ethyl acetate or methylene chloride andmethanol. Reverse phase preparative HPLC was carried out using aShimadzu Preparative HPLC system running Discovery VP software usingMethod A: YMC Sunfire 5 m C18 30×100 mm column with a 10 min gradient at40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA;B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm), Method B:PHENOMENEX® Luna Axia 5 m C18 30×75 mm column with a 10 min gradient at40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1%TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), Method C:PHENOMENEX® Luna 5 μm C18 30×100 mm column with a 10 min gradient at 40mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1%TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), or MethodD: PHENOMENEX® Luna 5 μm C18 30×100 mm column with a 10 min gradient at40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA;B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).

Alternatively, reverse phase preparative HPLC was carried out using aVarian ProStar Preparative HPLC System running Star 6.2 ChromatographyWorkstation software using Method E: Dynamax 10 μm C18 41.4×250 mmcolumn with a 30 min gradient at 30 mL/min from 10% B to 100% B (A 98%water, 2% acetonitrile, 0.05% TFA; B: 98% acetonitrile, 2% water, 0.05%TFA, UV 254 nm).

LCMS chromatograms were obtained on a Shimadzu HPLC system runningDiscovery VP software, coupled with a Waters ZQ mass spectrometerrunning MassLynx version 3.5 software and using the following respectivemethods. Unless specified otherwise, for each method, the LC column wasmaintained at room temperature and UV detection was set to 220 nm.

Method A: A linear gradient using solvent A (10% methanol, 90% water,0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA);0-100% of solvent B over 4 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 5 μm C18 (4.5×50 mm). Flow rate was 4 mL/min.

Method B: A linear gradient using solvent A (10% methanol, 90% water,0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA);0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 5 μm C18 (2.0×30 mm). Flow rate was 1 mL/min.

Method C: A linear gradient using solvent A (10% acetonitrile, 90%water, 10 mM NH₄OAc) and solvent B (90% acetonitrile, 10% water, 10 mMNH₄OAc); 0-100% of solvent B over 4 min and then 100% of solvent B over1 min. Column: PHENOMENEX® Luna 5 μm C18 (4.5×50 mm). Flow rate was 4mL/min.

Method D: A linear gradient using solvent A (10% acetonitrile, 90%water, 0.05% of TFA) and solvent B (90% acetonitrile, 10% water, 0.05%of TFA); 0-100% of solvent B over 2 min and then 100% of solvent B over1 min. Column: Luna 5 m C18 (4.5×30 mm). Flow rate was 1 mL/min.

Method E: A linear gradient using solvent A (10% MeOH, 90% water, 10 mMNH₄OAc) and solvent B (90% MeOH, 10% water, 10 mM NH₄OAc); 0-100% ofsolvent B over 4 min and then 100% of solvent B over 1 min. Column:PHENOMENEX® Luna 5 μm C18 (4.5×50 mm). Flow rate was 4 mL/min.

Method F: A linear gradient using solvent A (10 mM ammonium acetate, 95%water, 5% ACN) and solvent B (10 mM ammonium acetate, 95% ACN, 5%water); 0-100% of solvent B over 4 min and then 100% of solvent B over 1min. Column: Mac-Mod Halo (C18, 4.6×50 mm). Flow rate was 4 mL/min.

Method G: A linear gradient using solvent A (10% acetonitrile, 90%water, 0.1% TFA) and solvent B (90% acetonitrile, 10% water, 0.1% TFA);0-100% of solvent B over 4 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 3 μm C18 (2.0×50 mm). Flow rate was 4 mL/min.

Method H: A linear gradient using solvent A (10% methanol, 90% water,0.1% of formic acid) and solvent B (90% methanol, 10% water, 0.1% offormic acid); 0-100% of solvent B over 2 min and then 100% of solvent Bover 1 min. Column: PHENOMENEX® Luna 3 μm C18 (2.0×30 mm). Flow rate was1 mL/min.

Method I: A linear gradient using solvent A (10% MeOH, 90% water, 10 mMNH₄OAc) and solvent B (90% MeOH, 10% water, 10 mM NH₄OAc); 0-100% ofsolvent B over 2 min and then 100% of solvent B over 1 min. Column:PHENOMENEX® Luna 3 μm C18 (2.0×30 mm). Flow rate was 1 mL/min.

Method J: A linear gradient using solvent A (10% methanol, 90% water,0.1% of formic acid) and solvent B (90% methanol, 10% water, 0.1% ofTFA); 0-100% of solvent B over 4 min and then 100% of solvent B over 1min. Column: PHENOMENEX® Luna 5 μm C18 (4.5×50 mm). Flow rate was 4mL/min.

Method K: A linear gradient using solvent A (10 mM ammonium acetate, 95%water, 5% ACN) and solvent B (10 mM ammonium acetate, 95% ACN, 5%water); 0-100% of solvent B over 5.5 min and then 100% of solvent B over1.5 min. Column: SUPELCO® Ascentis 4.6×50 mm 2.7 μm C18. Flow rate was 4mL/min.

Method L: A linear gradient using solvent A (5% methanol, 95% water,0.05% of TFA) and solvent B (95% methanol, 5% water, 0.05% of TFA);0-100% of solvent B over 4 min and then 100% of solvent B over 1 min.Column: Waters XBridge C18 (4.6×50 mm, 5 μm). Flow rate was 4 mL/min.The LC column was maintained at 35° C.

Method M: A linear gradient using of Solvent A (0.05% TFA, 100% water)and Solvent B (0.05% TFA, 100% ACN); 2 to 98% B over 1 min, with 0.5 minhold time at 98% B. Column: Waters BEH C18 (2.1×50 mm). Flow rate: 0.8mL/min.

Preparative HPLC methods employed in the purification of products:

Method A: Linear gradient of 0 to 100% B over 10 min, with 5 min holdtime at 100% B; Shimadzu LC-8A binary pumps

Waters ZQ mass spectrometer using Waters Masslynx 4.0 SP4 MS software

UV visualization at 220 nm

Column: Waters XBridge 19×150 mm 5 m C18

Flow rate: 20 ml/min

Peak collection triggered by mass spectrometry

Solvent A: 0.1% TFA, 10% ACN, 90% water

Solvent B: 0.1% TFA, 90% ACN, 10% water

In addition, the following orthogonal HPLC conditions were used to checkthe purity of the compounds:

Method A: A linear gradient using solvent A (5% acetonitrile, 95% water,0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA);10-100% of solvent B over 10 min and then 100% of solvent B over 5 min.Column: Sunfire C18 3.5 μm (4.6×150 mm). Flow rate was 2 ml/min. and UVdetection was set to 220 nm. The LC column was maintained at roomtemperature.

Method B: A linear gradient using solvent A (5% acetonitrile, 95% water,0.05% TFA) and solvent B (95% acetonitrile, 5% water, 0.05% TFA);10-100% of solvent B over 10 min and then 100% of solvent B over 5 min.Column: Xbridge Phenyl 3.5m (4.6×150 mm). Flow rate was 2 ml/min. and UVdetection was set to 220 nm. The LC column was maintained at roomtemperature.

NMR Employed in Characterization of Examples

¹H NMR spectra were obtained with Bruker or JEOL Fourier transformspectrometers operating at frequencies as follows: ¹H NMR: 400 MHz(Bruker or JEOL) or 500 MHz (JEOL). ¹³C NMR: 100 MHz (Bruker or JEOL).Spectra data are reported in the format: chemical shift (multiplicity,coupling constants, number of hydrogens). Chemical shifts are specifiedin ppm downfield of a tetramethylsilane internal standard (δ units,tetramethylsilane=0 ppm) and/or referenced to solvent peaks, which in ¹HNMR spectra appear at 2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, and7.24 ppm for CHCl₃, and which in ¹³C NMR spectra appear at 39.7 ppm forCD₃SOCD₃, 49.0 ppm for CD₃OD, and 77.0 ppm for CDCl₃. All ¹³C NMRspectra were proton decoupled.

Biology

The endothelium occupies a pivotal position at the interface between thecirculating humoral and cellular elements of the blood, and the solidtissues which constitute the various organs. In this unique position,endothelial cells regulate a large number of critical processes,including leukocyte adherence and transit through the blood vessel wall,local control of blood vessel tone, modulation of the immune response,the balance between thrombosis and thrombolysis, and new blood vesseldevelopment. Thus, endothelial cell dysfunction has been postulated as acentral feature of vascular diseases such as hypertension andatherosclerosis. (WO 1999/032611 and references cited therein, e.g.,Folkman, J. et al., Science, 235:442-447 (1987); Yanagisawa, M. et al.,Nature, 332(6163):411-415 (1988); Folkman, J. et al., J. Biol. Chem.,267(16):10931-10934 (1992); Janssens, S. P. et al., J. Biol. Chem.,267(21):14519-14522 (1992); Lamas, S. et al., Proc. Natl. Acad. Sci.U.S.A., 89(14):6348-6352 (1992); Luscher, T. F. et al., Hypertension,19(2):117-130 (1992); Williams et al., Am. Rev. Respir. Dis.,146:S45-S50 (1992); and Bevilacqua, M. P. et al., J. Clin. Invest.,91(2):379-387 (1993)).

Atherosclerosis and its associated coronary artery disease (CAD) is theleading cause of mortality in the industrialized world. Despite attemptsto modify secondary risk factors (smoking, obesity, lack of exercise)and treatment of dyslipidemia with dietary modification and drugtherapy, coronary heart disease (CHD) remains the most common cause ofdeath in the U.S., where cardiovascular disease accounts for 44% of alldeaths, with 53% of these associated with atherosclerotic coronary heartdisease.

Risk for development of atherosclerosis has been shown to be stronglycorrelated with certain plasma lipid levels. While elevated low densitylipoprotein-cholesterol (LDL-C) may be the most recognized form ofdyslipidemia, it is by no means the only significant lipid associatedcontributor to CHD. Low high density lipoprotein-cholesterol (HDL-C) isalso a known risk factor for CHD (Gordon, D. J. et al., Circulation,79(1):8-15 (1989)).

High LDL-C and triglyceride levels are positively correlated, while highlevels of HDL-C are negatively correlated with the risk for developingcardiovascular diseases. Thus, dyslipidemia is not a unitary riskprofile for CHD but may be comprised of one or more, preferably one tothree, lipid aberrations.

At least 50% of the variation in HDL cholesterol levels is geneticallydetermined. The phenotype of elevated HDL cholesterol is oftendominantly inherited, but homozygous deficiency of HL or of thecholesteryl ester transfer protein (CETP), which result in elevated HDLcholesterol, are recessive conditions. Recently, several geneticvariations in the human endothelial lipase gene have been identified,six of which potentially produce functional variants of the protein, andthe frequencies of these variants were found to be associated withelevated levels of HDL cholesterol in human subjects (deLemos, A. S. etal., Circulation, 106(11):1321-1326 (2002)). Notably, the endotheliallipase-mediated binding and uptake of HDL particles and the selectiveuptake of HDL-derived cholesterol esters have been reported to beindependent of its enzymatic lipolytic activity (Strauss, J. G. et al.,Biochem. J., 368:69-79 (2002)).

Because of the beneficial effects widely associated with elevated HDLlevels, an agent which inhibits EL activity in humans, by virtue of itsHDL increasing ability, are expected to be useful for the treatment,prevention, the arrestment and/or regression of atherosclerosis,coronary heart disease, cerebrovascular disorders etc., especially those(but not restricted thereto) which are characterized by one or more ofthe following factors: (a) high plasma triglyceride concentrations, highpostprandial plasma triglyceride concentrations; (b) low HDL cholesterolconcentration; (c) low apoA lipoprotein concentrations; (d) high LDLcholesterol concentrations; (e) small dense LDL cholesterol particles;and (f) high apoB lipoprotein concentrations.

The term “modulator” refers to a chemical compound with capacity toeither enhance (e.g., “agonist” activity) or partially enhance (e.g.,“partial agonist” activity) or inhibit (e.g., “antagonist” activity or“inverse agonist” activity) a functional property of biological activityor process (e.g., enzyme activity or receptor binding); such enhancementor inhibition may be contingent on the occurrence of a specific event,such as activation of a signal transduction pathway, receptorinternalization, and/or may be manifest only in particular cell types.

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known anti-atherosclerosisagents, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with ananti-atherosclerosis agent, e.g., an endothelial lipase inhibitor.Exemplary subjects include human beings of any age with risk factors foratherosclerosis and its associated coronary artery disease. Common riskfactors include, but are not limited to, age, sex, weight, and familyhistory.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” covers the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit endothelial lipase and/or to preventor treat the disorders listed herein. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe preventive or therapeutic effect, whether administered incombination, serially, or simultaneously.

Biological Activity

Endothelial lipase activity was measured using a fluorescent substrate,A10070, (Invitrogen, CA) doped into an artificial vesicle containingDMPG (Avanti Polar Lipids) as the excipient. Vesicles were prepared bycombining 285 μL of 1 mM DMPG in a 1:1 mixture of MeOH and CHCl₃ with 15μL of 1 mM A10070 in a 1:1 mixture of MeOH and CHCl₃. The mixture wasdried under nitrogen and resuspended in 150 μL of 50 mM HEPES pH 8.0buffer containing 100 mM NaCl and 0.2 mM EDTA. The sample was allowed tosit at rt for 15 min and then was sonicated 3×4 mins on ice with aBranson Sonicator using duty cycle 1. This preparation provides vesicleswith a mole fraction of 0.05 for the FRET substrate.

The enzymatic assay was measured using white, opaque 96-well half areaplates. Each well contained 60 μL of assay buffer (50 mM HEPES pH 8.0,50 mM NaCl and 1 mM CaCl₂) and 2 ul of a DMSO solution containingcompound of interest. Conditioned media obtained from HT-1080 cells,which were transformed by RAGE technology (Athersys) to overexpressendogenous EL, was added and the reaction was allowed to incubate for 20min at 37° C. with gentle agitation. The reaction was started by theaddition of 20 μL of a 1:4 dilution of vesicles. The final totalreaction volume was 100 μL. The reaction rates were measured on a Geminiplate reader with an excitation wavelength of 488 nm and an emission of530 nm. Readings were taken every 20 seconds for 10 min with agitationbetween each reading. The slope of the linear portion of the readout wasused to calculate the rate of the reaction.

The exemplified examples disclosed in the present invention were testedin the EL assay described above and found having EL inhibitory activity.A range of EL IC₅₀ values of ≦10 μM (10000 nM) was observed for Examples1-14, 16-71 and 73-299. The EL IC₅₀ values measured for the followingexamples are listed in Table 1.

TABLE 1 Ex. No. EL IC₅₀ (nM) 14 2779 15 12980 24 568 25 1058 26 9855 323738 45 3372 46 3317 48 447 53 18 54 7157 57 4890 72 22160 73 468 1171190 125 329 127 30 128 13 135 3684 136 19 137 848 138 1724 139 28 14239 158 525 163 2250 164 788 171 1477 175 496 176 1089 180 141 181 6440184 5706 186 42 187 946 189 641 190 276 202 1905 203 6220 208 659 209512 211 291 216 3483 218 296 225 5277 231 3841 234 439 240 24 243 967258 10 259 10 267 1418 280 3140 281 875 289 10 299 9562

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to,atherosclerosis, coronary heart disease, coronary artery disease,coronary vascular disease, cerebrovascular disorders, Alzheimer'sdisease, venous thrombosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia.

VI. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions, syrups, and emulsions; sublingually; bucally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection, or infusion techniques (e.g., as sterile injectable aqueousor non-aqueous solutions or suspensions); nasally, includingadministration to the nasal membranes, such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories. They can be administered alone, butgenerally will be administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, anti-bacterialagents, anti-fungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.01 to about 5000 mg per day, preferably between about 0.1 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more, preferably one to three, other therapeutic agent(s),e.g., HMG-CoA reductase inhibitors or other pharmaceutically activematerial.

The compounds of the present invention may be employed in combinationwith other EL inhibitors or one or more, preferably one to three, othersuitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-atherosclerotic agents,anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemicagents, anti-hyperinsulinemic agents, anti-thrombotic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-ischemic agents, anti-hypertensive agents, anti-obesityagents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, memoryenhancing agents, anti-dementia agents, cognition promoting agents,appetite suppressants, treatments for heart failure, treatments forperipheral arterial disease, treatment for malignant tumors, andanti-inflammatory agents.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingatherosclerosis: anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), acyl-coenzyme A:cholesterolacyltransferase (ACAT) inhibitors, LXR agonist, probucol, raloxifene,nicotinic acid, niacinamide, cholesterol absorption inhibitors, bileacid sequestrants (such as anion exchange resins, or quaternary amines(e.g., cholestyramine or colestipol)), low density lipoprotein receptorinducers, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidant vitamins,(β-blockers, anti-diabetes agents, angiotensin II antagonists,angiotensin converting enzyme inhibitors, platelet aggregationinhibitors, fibrinogen receptor antagonists, aspirin or fibric acidderivatives.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingcholesterol biosynthesis inhibitor, particularly an HMG-CoA reductaseinhibitor. Examples of suitable HMG-CoA reductase inhibitors include,but are not limited to, lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin, and rivastatin.

The term HMG-CoA reductase inhibitor is intended to include allpharmaceutically acceptable salt, ester, free acid and lactone forms ofcompounds which have HMG-CoA reductase inhibitory activity and,therefore, the use of such salts, esters, free acids and lactone formsis included within the scope of this invention. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identifiedusing assays well-known in the art.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenoreceptoragonist agents; sibutramine, gastrointestinal lipase inhibitors (such asorlistat), and leptins. Other agents used in treating obesity orobesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more, preferably one to three, additionaltherapeutic agents. By “administered in combination” or “combinationtherapy” it is meant that the compound of the present invention and oneor more, preferably one to three, additional therapeutic agents areadministered concurrently to the mammal being treated. When administeredin combination, each component may be administered at the same time orsequentially in any order at different points in time. Thus, eachcomponent may be administered separately but sufficiently closely intime so as to provide the desired therapeutic effect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the endothelial lipase. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving endothelial lipase or HDL activity. For example, acompound of the present invention could be used as a reference in anassay to compare its known activity to a compound with an unknownactivity. This would ensure the experimenter that the assay was beingperformed properly and provide a basis for comparison, especially if thetest compound was a derivative of the reference compound. Whendeveloping new assays or protocols, compounds according to the presentinvention could be used to test their effectiveness. The compounds ofthe present invention may also be used in diagnostic assays involvingendothelial lipase.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of dyslipidemias andthe sequelae thereof. In another embodiment, the package insert statesthat the pharmaceutical composition can be used in combination (asdefined previously) with a second therapeutic agent for the treatmentand/or prophylaxis of dyslipidemias and the sequelae thereof. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention should become apparent in the course ofthe above descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following examples demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention.

Intermediate 1. Cis-4-phenylcyclohexanamine

Intermediate 1A. Cis-N-benzhydryl-4-phenylcyclohexanamine: To a solutionof 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine(526 mg, 2.87 mmol) in DCE (4 mL) at 0° C. was added sodiumtriacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A whitesuspension resulted and was stirred for 5 min before the ice-water bathwas removed. The reaction was stirred at rt for 1.5 h. The reaction wasquenched with water carefully, then saturated NaHCO₃ was added carefullyand the aqueous portion was extracted with DCM (3×). The organic layerswere combined, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (0-100%hexane/EtOAc) to give Intermediate 1A (734 mg, 2.15 mmol, 74.9% yield)and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.559 mmol,19.5% yield), LC-MS (ESI) m/z 342.1 (M+H), RT=1.76 min (Method B). ¹HNMR (400 MHz, chloroform-d) δ ppm 7.37 (4H, d, J=7.33 Hz), 7.23-7.31(6H, m), 7.11-7.23 (5H, m), 4.91 (1H, s), 2.80-2.88 (1H, m), 2.46-2.56(1H, m), 1.74-1.90 (4H, m), 1.60-1.70 (2H, m), 1.47-1.59 (2H, m).

Intermediate 1

To a solution of Intermediate 1A (714 mg, 2.09 mmol) in MeOH (20 mL) andEtOAc (5 mL) were added 10% palladium on carbon (71.4 mg, 0.0670 mmol)and acetic acid (0.120 mL, 2.09 mmol). The reaction was stirred under H₂balloon for 3 h. The reaction mixture was filtered through Celite® andrinsed with EtOAc. The filtrate was concentrated, re-dissolved in DCM,and the organic layer was extracted with 1 N HCl. The combined aqueousportions were made basic with 1 N NaOH and extracted with DCM (3×). Thecombined organic portions were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give Intermediate 1 (321 mg, 1.83 mmol,88.0% yield) as a colorless wax. LC-MS (ESI) m/z 176.1 (M+H), RT=1.43min (Method B). ¹H NMR (400 MHz, DMSO-d) δ ppm 7.24-7.30 (4H, m),7.13-7.18 (1H, m), 3.10-3.16 (1H, m), 2.42-2.50 (1H, m), 1.80-1.93 (2H,m), 1.60-1.66 (4H, m), 1.44-1.54 (2H, m).

Intermediate 2. Cis-4-amino-1-(4-fluorophenyl)cyclohexanol

Intermediate 2 was prepared as a pink oil following the proceduredescribed for Intermediate 1 by replacing 4-phenylcyclohexanone with4-(4-fluorophenyl)-4-hydroxycyclohexanone. LC-MS (ESI) m/z 228.0 (M+H),RT=0.99 min (Method B).

Intermediate 3. Cis-4-(3-(trifluoromethyl)phenyl)cyclohexanaminehydrochloride

Intermediate 3A.8-(3-(Trifluoromethyl)phenyl)-1,4-dioxaspiro[4.5]decan-8-ol

To a round bottom flask was added n-BuLi (3.84 mL, 9.60 mmol) at −78° C.under argon. THF (10 mL) was added followed by addition of1-bromo-3-(trifluoromethyl)benzene (0.884 mL, 6.40 mmol) in THF (1 mL).The reaction mixture was stirred for 30 minutes at −78° C. A solution of1,4-dioxaspiro[4.5]decan-8-one (1.00 g, 6.40 mmol) in THF (5 mL) wasthen added dropwise to the reaction mixture at −70° C. The reaction wasstirred for 1 h at −70° C., and then quenched by the addition of 1 NHCl. The reaction mixture was extracted with EtOAc and the organicportions were separated and combined. The organic layer was dried overNa₂SO₄, filtered, and concentrated to give Intermediate 3A (1.87 g, 6.19mmol, 97.0% yield). LCMS=325 [M+Na], RT=1.89 minutes (Method B).

Intermediate 3B.8-(3-(Trifluoromethyl)phenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a solution of Intermediate 3A (1.87 g, 6.19 mmol) and Et₃N (1.724 mL,12.37 mmol) in DCM (30 mL) was added a solution of methanesulfonylchloride (0.53 mL, 6.8 mmol) in DCM (10 mL) over 1 h at rt. The reactionmixture was stirred at rt for 2.5 h. Additional Et₃N (1.724 mL, 12.37mmol) and methanesulfonyl chloride (0.53 mL, 6.8 mmol) were added andstirred for another 1 h. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was dried over Na₂SO₄, filtered and thesolvent was evaporated under reduced pressure to give Intermediate 3B(1.7 g, 5.9 mmol, 97% yield). LC-MS (ESI) m/z 285 (M+H), RT=3.43 min(Method C).

Intermediate 3C. 4-(3-(Trifluoromethyl)phenyl)cyclohex-3-enone

To a solution of Intermediate 3B (1.00 g, 3.52 mmol) in DCM (5 mL) wasadded TFA (2.5 mL, 32. mmol). The reaction was stirred at rt for 2 h.The reaction mixture was concentrated and purified on a 24 g silica gelcolumn eluted from 0 to 100% EtOAc in hexanes over 15 minutes toIntermediate 3C (650 mg, 2.71 mmol, 77.0% yield). LCMS=241 [M+1],RT=3.59 min (Method A).

Intermediate 3D. 4-(3-(Trifluoromethyl)phenyl)cyclohexanone

To a solution of Intermediate 3C (650 mg, 2.71 mmol) in EtOAc (10 mL)was added Pd/C (0.15 g, 0.27 mmol) in a pressure bottle. The mixture wasstirred under 45 psi of hydrogen for 16 h. The catalyst was carefullyfiltered under nitrogen and the solvent was removed under vacuum. Theresidue was dissolved in DCM (10 mL) and Dess-Martin periodinane (1.26g, 2.98 mmol) was added as one single portion. The reaction mixture wasstirred at rt for 3 h. The reaction mixture was diluted with DCM, washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crude waspurified by flash chromatography on a 24 g cartridge with 0 to 100%EtOAc in hexanes over 15 min to give Intermediate 3D (276 mg, 1.14 mmol,42.1% yield). LCMS, RT=2.01 min (Method B).

Intermediate 3

Intermediate 3 was prepared as a pink oil following the proceduredescribed for Intermediate 1 by replacing 4-phenylcyclohexanone withIntermediate 3D. The product was dissolved in Et₂O and 4N HCl in dioxane(100 μL) was added. The resulting precipitate was collected byfiltration. The solid was pumped to dryness to give Intermediate 3 (88mg, 75% yield). LC-MS (ESI) m/z 244 (M+H), RT=1.68 min (Method B).

Intermediate 4. (R)-6-(Trifluoromethyl)-2,3-dihydro-1H-inden-1-aminehydrochloride

Intermediate 4A.(R)-2-Methyl-N-(6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ylidene)propane-2-sulfinamide

To a stirred solution of (R)-2-methylpropane-2-sulfinamide (578 mg, 4.77mmol) and 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (1.00 g, 5.00mmol) in THF (4 mL) at rt was added tetraethoxytitanium (1.88 mL, 9.08mmol). The reaction mixture was heated at 75° C. for 16 h. The reactionmixture was allowed to cool and used directly in the next step. LC-MS(ESI) 304.0 (M+H), RT=2.20 min (Method B).

Intermediate 4B.(R)-2-Methyl-N—((R)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfinamide

Sodium borohydride (756 mg, 20.0 mmol) was stirred in a round-bottomedflask under argon at −40 to −50° C. The reaction mixture of Intermediate4A was added dropwise to the flask, and THF was added to the reactionmixture (ca. 0.6 M). The resulting mixture was allowed to warm up to 0°C. during 1.5 h period. The reaction mixture was cooled in dry ice andMeOH was added dropwise until gas evolution stopped. The mixture wasstirred at rt for 20 min, filtered through Celite and rinsed with EtOActhen CH₂Cl₂. The filtrate was washed with brine (2×) and dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography (hexanes/EtOAc) to give Intermediate 4B (370 mg, 1.21mmol, 26.7% yield) as colorless crystals. LC-MS (ESI) 306.0 (M+H),RT=2.10 min (Method B).

Intermediate 4

Intermediate 4B (370 mg, 1.21 mmol) was stirred in MeOH (5 mL) at rt. 4N HCl in dioxane (2 mL) was added. The resulting mixture was stirred atrt for 20 min. The solvents were evaporated and CH₂Cl₂(3×) was added andevaporated. The resulting white solids were vacuum dried for 1 h to giveIntermediate 4 (84 mg, 0.35 mmol, 29% yield). The HCl salt was useddirectly in the next step. ¹H NMR (400 MHz, MeOD) δ ppm 7.57 (1H, d,J=7.8 Hz), 7.47 (1H, d, J=7.6 Hz), 7.25 (1H, t, J=7.8 Hz), 4.88 (1H, dd,J=7.8, 4.8 Hz), 3.09-3.23 (1H, m), 2.90-3.08 (1H, m), 2.64 (1H, dddd,J=14.1, 8.5, 8.3, 5.7 Hz), 2.01-2.23 (1H, m, J=14.1, 8.7, 5.3, 5.3 Hz).

Intermediates 5-12 were prepared according to the procedures describedin Intermediate 4 using the appropriate indanone or tetraline-1-one asthe starting material.

Intermediate LC-MS No. Structure Name [M + 1]/RT 5

(R)-5-(trifluoromethyl)-2,3- dihydro-1H-inden-1-amine hydrochloride185.0 (M- NH₃ + H)/1.42 min (Method B) 6

(R)-4-(trifluoromethyl)-2,3- dihydro-1H-inden-1-amine hydrochloride185.0 (M- NH₃ + H)/1.38 min (Method B) 7

(R)-4,6-dichloro-2,3- dihydro-1H-inden-1-amine hydrochloride 186.9 (M-NH₃ + H)/1.50 min (Method B) 8

(S)-6-(trifluoromethyl)-2,3- dihydro-1H-inden-1-amine hydrochloride185.0 (M- NH₃ + H)/1.32 min (Method B) 9

(R)-4-bromo-2,3-dihydro- 1H-inden-1-amine hydrochloride 196.9 (M- NH₃ +H)/1.34 min (Method B) 10

(R)-5-bromo-2,3-dihydro- 1H-inden-1-amine hydrochloride 196.9 (M- NH₃ +H)/1.30 min (Method B) 11

(R)-6-bromo-2,3-dihydro- 1H-inden-1-amine hydrochloride 196.9 (M- NH₃ +H)/1.25 min (Method B) 12

(R)-4,4-dimethyl-1,2,3,4- tetrahydronaphthalen-1- amine hydrochloride159.1 (M- NH₃ + H)/1.42 min (Method B)

Intermediate 13.(S)-5-(2,2,2-Trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-amine

Intermediate 13A.(R,Z)-2-Methyl-N-(5-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalen-1(2H)-ylidene)propane-2-sulfinamide

To a stirring solution of 2-methylpropane-2-sulfinamide (339 mg, 2.79mmol) and 5-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalen-1(2H)-one (650mg, 2.66 mmol) in THF (3 mL) was added tetraethoxytitanium (1.10 mL,5.32 mmol) at rt. The reaction mixture was heated at 75° C. for 14 h.The reaction mixture was cooled to give Intermediate 13A which was useddirectly in the next step. LCMS=3.86 min [M+1]=347 (Method B).

Intermediate 13B.(R)-2-Methyl-N—((S)-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)propane-2-sulfinamide

To a suspension of L-Selectride (3.90 mL, 3.90 mmol) in THF (1 mL) wasadded Intermediate 13A (0.45 g, 1.3 mmol) in THF (1 mL) at −50° C. Thereaction mixture was warmed up to rt until the reduction was complete.To the reaction mixture was added MeOH (2 mL) and brine (2 mL). Theresulting reaction mixture was stirred for 5 minutes, filtered, and thefiltrate was concentrated in vacuo. The crude product was dissolved in asmall amount of DCM and loaded on a 4 g silica gel cartridge elutingfrom 0 to 100% EtOAc in hexanes over 15 minutes to give Intermediate 13B(196 mg, 0.561 mmol, 43.1% yield). LCMS=2.09 min [M+1]=350 (Method B).

Intermediate 13

To a solution of Intermediate 13B (245 mg, 0.701 mmol) in DCM (1 mL) wasadded 4 N HCl (175 μl, 0.701 mmol) in dioxane. The resulting mixture wasstirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) wasadded and evaporated. The resulting white solid was vacuum dried for 1 hto give Intermediate 13 (140 mg, 0.571 mmol, 81.0% yield) as a HCl saltwhich was used directly without further purification. LCMS=1.48 min[M+1-17]=229 (Method B).

Intermediate 14.(R)-5-(2,2,2-Trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-amine

Intermediate 14A.(R)-2-Methyl-N—((R)-5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)propane-2-sulfinamide

To a suspension of NaBH₄ (197 mg, 5.20 mmol) in THF was addedIntermediate 21A (0.45 g, 1.3 mmol) in THF (1 mL) at −50° C. Thereaction mixture was warm up to rt until the reduction was complete. Thereaction mixture was added MeOH (1 mL) and equal amount of brine. Thereaction was stirred for 5 minutes and filtered The filtrate wasconcentrated in vacuo. The crude product was dissolved in a small amountof DCM and loaded on a 4 g cartridge eluting from 0 to 100% EtOAc inhexanes over 15 minutes to give Intermediate 14A (245 mg, 0.701 mmol,53.9% yield). LCMS=2.09 min [M+1]=350 (Method B).

Intermediate 14

To a solution of Intermediate 14A (206 mg, 0.590 mmol) in DCM (1 mL) wasadded 4 N HCl (147 μl, 0.590 mmol) in dioxane. The resulting mixture wasstirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) wasadded and evaporated. The resulting white solid was vacuum dried for 1 hto give Intermediate 14 (0.13 mg, 0.51 mmol, 86% yield) in HCl saltwhich was used directly without further purification. LCMS=1.55 min[M+1-17]=229 (Method B).

Intermediates 15-24HCl salts were prepared according to the proceduresdescribed in Intermediate 13-14 using the appropriate tetralin-1-one asthe starting material.

Intermediate LC-MS No. Structure Name [M + 1]/RT 15

(R)-6-((trifluoromethoxy) methyl)-1,2,3,4- tetrahydronaphthalen-1- amine229.0 (M-NH₃ + H)/ 1.15 min (Method D) 16

(S)-6-((trifluoromethoxy) methyl)-1,2,3,4- tetrahydronaphthalen-1- amine229.0 (M-NH₃ + H)/ 1.17 min (Method D) 17

(R)-7-fluoro-1,2,3,4- tetrahydronaphthalen-1- amine 149.0 (M-NH₃ + H)/1.20 min (Method B) 18

(S)-7-fluoro-1,2,3,4- tetrahydronaphthalen-1- amine 149.0 (M-NH₃ + H)/1.19 min (Method B) 19

(R)-5-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 199.0(M-NH₃ + H)/ 1.53 min (Method B) 20

(S)-5-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 199.0(M-NH₃ + H)/ 1.53 min (Method B) 21

(R)-6-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 199.1(M-NH₃ + H)/ 1.54 min (Method B) 22

(S)-6-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 199.1(M-NH₃ + H)/ 1.54 min (Method B) 23

(R)-7-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 216.0(M + H)/1.38 min (Method B) 24

(S)-7-(trifluoromethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine 216.1(M + H)/1.37 min (Method B)

Intermediate 25. (1R,4R)-4-Phenyl-1,2,3,4-tetrahydronaphthalen-1-amine

and

Intermediate 26. (1R,4S)-4-Phenyl-1,2,3,4-tetrahydronaphthalen-1-amine

Intermediate 25A.(R)-2-Methyl-N-((1R,4R)-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)propane-2-sulfinamideand Intermediate 26A.(R)-2-methyl-N-((1R,4S)-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)propane-2-sulfinamide

To a stirring solution of 2-methylpropane-2-sulfinamide (0.818 g, 6.75mmol) and 4-phenyl-3,4-dihydronaphthalen-1(2H)-one (1.5 g, 6.8 mmol) inTHF (3.5 mL) at rt was added tetraethoxytitanium (2.80 mL, 13.5 mmol).The reaction mixture was heated at 75° C. for 14 h. The reaction mixturewas cooled and used directly in the next step. Sodium borohydride (1.12g, 29.7 mmol) was stirred in a round-bottomed flask under argon at −40to −50° C. The reaction of(R)-2-methyl-N-(4-phenyl-3,4-dihydronaphthalen-1(2H)-ylidene)propane-2-sulfinamidewas added dropwise to the reaction mixture. The resulting mixture waswarmed up to 0° C. during 1.5 h period. It was cooled in dry ice andMeOH was added dropwise till gas evolution stopped, followed by theaddition of brine. The white suspension was filtered through Celite,rinsed several times with EtOAc and DCM. The filtrate was concentratedand re-dissolved in DCM, washed with brine, dried over Na₂SO₄ andconcentrated. The reaction mixture was purified by flash chromatography(0-50% EtOAc/hexanes) to give a pale yellow crystalline solid (1.1 g).This material was submitted for chiral separation on SFC (Instrument:Berger SFC MGII; Column: CHIRALCEL® OJ-H, 250×30 mm ID, 5 micron; Flowrate: 100 mL/min, 100 bar BP, 35° C.; Mobile Phase: 85/15CO₂/Isopropanol-0.1 v/v % DEA; Detector Wavelength: 220 nm; SampleSolution: 1100 mg/21.6 mL (6 parts ACN:4 parts IPA) (51 mg/mL);Injection Size: 1.5 mL) to give Intermediate 25A (the fast eluent, 460mg, 1.41 mmol, 20.8% yield) as a colorless viscous oil and Intermediate26A (the slow eluent, 508 mg, 1.55 mmol, 23.0% yield) as a white solid.

Intermediate 25A: LC-MS (ESI) m/z 328.1 (M+H), RT=2.24 min (Method B).¹H NMR (500 MHz, chloroform-d) d ppm 7.46 (1H, d, J=6.88 Hz), 7.29-7.35(2H, m), 7.21-7.27 (2H, m), 7.10-7.17 (3H, m), 6.86 (1H, d, J=7.70 Hz),4.67 (1H, q, J=3.58 Hz), 4.02 (1H, dd, J=9.77, 5.91 Hz), 3.30 (1H, d,J=1.93 Hz), 2.08-2.20 (2H, m), 2.01-2.08 (1H, m), 1.92-2.01 (1H, m),1.25 (9H, s).

Intermediate 26A: LC-MS (ESI) m/z 328.1 (M+H), RT=2.24 min (Method B).¹H NMR (500 MHz, chloroform-d) d ppm 7.58 (1H, d, J=7.43 Hz), 7.24-7.30(3H, m), 7.14-7.22 (2H, m), 7.00 (2H, d, J=7.15 Hz), 6.93 (1H, d, J=7.98Hz), 4.68 (1H, q, J=4.59 Hz), 4.20 (1H, t, J=5.50 Hz), 3.32 (1H, d,J=3.85 Hz), 2.32-2.42 (1H, m), 1.99-2.09 (1H, m), 1.79-1.89 (2H, m),1.25 (9H, s).

Intermediate 25

Intermediate 25A (450 mg, 1.37 mmol) was stirred in MeOH (5 mL) at rt. 4N HCl in dioxane (0.344 mL, 1.37 mmol) was added. The resulting mixturewas stirred at rt for 0.5 h. The solvents were evaporated and CH₂Cl₂(3×)was added and evaporated. The resulting white solids were vacuum driedfor 1 h to give Intermediate 25 (409 mg, 1.57 mmol, 115% yield). LC-MS(ESI) m/z 207.1 (M−NH₃+H), RT=1.66 min (Method B). ¹H NMR (400 MHz,MeOD) δ ppm 7.57 (1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.6 Hz), 7.25 (1H, t,J=7.8 Hz), 4.88 (1H, dd, J=7.8, 4.8 Hz), 3.09-3.23 (1H, m), 2.90-3.08(1H, m), 2.64 (1H, dddd, J=14.1, 8.5, 8.3, 5.7 Hz), 2.01-2.23 (1H, m,J=14.1, 8.7, 5.3, 5.3 Hz).

Intermediate 26

Intermediate 26 was prepared using the procedure described forIntermediate 25 from Intermediate 26A. LC-MS (ESI) m/z 207.1 (M−NH₃+H),RT=1.64 min (Method B).

Intermediates 27-30 were prepared according to the procedures describedin Intermediate 25-26 using the appropriate tetralin-1-one as thestarting material.

Intermediate No. Structure Name LC-MS [M + 1]/RT 27

(1R,4R)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydronaphthalen-1- amine275.0 (M-NH₃ + H)/ 1.92 min (Method B) 28

(1R,4S)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydronaphthalen-1- amine275.0 (M-NH₃ + H)/ 1.92 min (Method B) 29

(1S,4S)-4-phenyl-1,2,3,4- tetrahydronaphthalen-1-amine 207.1 (M-NH₃ +H)/ 1.67 min (Method B) 30

(1S,4R)-4-phenyl-1,2,3,4- tetrahydronaphthalen-1-amine 207.1 (M-NH₃ +H)/ 1.68 min (Method B)

Intermediate 31. (1S,3S)-3-Phenyl-2,3-dihydro-1H-inden-1-aminehydrochloride and Intermediate 32.(1R,3R)-3-Phenyl-2,3-dihydro-1H-inden-1-amine hydrochloride

Intermediate 31A.(R)-2-Methyl-N-((1S,3S)-3-phenyl-2,3-dihydro-1H-inden-1-yl)propane-2-sulfinamideand Intermediate 32A.(R)-2-Methyl-N-((1R,3R)-3-phenyl-2,3-dihydro-1H-inden-1-yl)propane-2-sulfinamide

The mixture of Intermediate 31A and 32A was prepared by using similarprocedures as described for Intermediate 4B (0.55 g, 37%). LC-MS (ESI)314.0. (M+H), RT=2.23 min (Method B). The mixture was submitted tochiral SFC separation (Instrument: Berger Multigram II SFC; Column:CHIRALPAK® AD-H, 250×21 mm ID, 5 μm; Flow rate: 60 mL/min, 100 bar BP,35° C.; Mobile Phase: 15% Isopropanol/85% CO₂; Detector Wavelength: 220nm (lambda max); Injection Volume: 1000 μL; Sample Preparation: 500 mgin 10 mL (6 mL of IPA and 4 mL of MeCN, ˜50 mg/mL)) to give Intermediate31A (0.2 g, the fast eluant) and Intermediate 32A (0.2 g, the sloweluant) as white solids. Both intermediates were crystallized inMeOH/hexanes.

Intermediate 31 and Intermediate 32

Intermediate 31 and 32 were prepared in a similar procedure described inIntermediate 4.

Intermediate 31: LC-MS (ESI) 193.0 (M−NH₃+H), RT=1.62 min (Method B).

Intermediate 32: LC-MS (ESI) 193.0 (M−NH₃+H), RT=1.62 min (Method B).

Intermediate 33.Cis-4-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)cyclohexanamine

Intermediate 33A. (Z)-3,4-Dichloro-N′-hydroxybenzimidamide

A solution of 3,4-dichlorobenzonitrile (2.00 g, 11.6 mmol),hydroxylamine hydrochloride (1.65 mL, 12.8 mmol) and sodium hydroxide(4.15 mL, 12.4 mmol) in ethanol (40 mL) was stirred at rt for 1 h. Thereaction mixture was concentrated and refluxed in hexanes for 30 min andconcentrated in vacuo. The product, intermediate 33A was used directlywithout purification. HPLC/MS (Method C) retention time=1.24 min[M+H]⁺204.9.

Intermediate 33B. tert-Butylcis-4-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate

A microwave vial was charged withcis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.24 g, 0.98mmol), DMAP (0.12 g, 0.98 mmol) and Intermediate 33A (0.20 g, 0.98mmol). The reactants were dissolved in DMF (1 mL) and DIC (0.15 mL, 0.98mmol) was added. The reaction mixture was stirred at rt for 14 h. Thereaction mixture was diluted in 3 mL of pyridine. The vial was cappedand the reaction mixture was heated in the microwave at 145° C. for 20minutes, allowed to cool to rt, diluted with EtOAc and washed with waterand brine. The solution were concentrated under reduced pressure andpurified by flash chromatography with EtOAc/hexanes to give Intermediate33B (233 mg, 0.565 mmol, 57.9% yield) as a white solid. LCMS=434.1[M+1], RT=2.43 min (Method B); ¹H NMR (500 MHz, chloroform-d) δ ppm 8.19(1H, d, J=1.93 Hz), 7.92 (1H, dd, J=8.53, 1.93 Hz), 7.56 (1H, d, J=8.25Hz), 4.59 (1H, br. s.), 3.71 (1H, d, J=9.63 Hz), 3.14-3.22 (1H, m),2.07-2.17 (2H, m), 1.92-2.02 (2H, m), 1.84 (2H, td, J=8.67, 4.13 Hz),1.62-1.73 (2H, m), 1.44 (9H, s).

Intermediate 33

To Intermediate 33B (50 mg, 0.12 mmol) in CH₂Cl₂(1 mL) was added TFA(2.00 mL, 26.0 mmol). The reaction was stirred at rt for 2 h. Thereaction mixture was quenched with saturated NaHCO₃ and extracted withDCM. The organic portions were combined, dried over Na₂SO₄, andconcentrated in vacuo to give Intermediate 33 which was used directlyfor the next step without any further purification. LCMS=312.0 [M+1],RT=1.86 min (Method B).

Intermediate 34. 5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

Intermediate 34A. (Z)-5-Methoxy-3,4-dihydronaphthalen-1(2H)-one oxime

To a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (200 mg, 1.14mmol) and hydroxylamine methyl ether hydrochloride (284 mg, 3.40 mmol)in MeOH (5 mL) was added sodium acetate (279 mg, 3.40 mmol). Thereaction mixture was heated at 60° C. for 1 h, cooled and partitionedbetween H₂O and EtOAc. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated in vacuo to give Intermediate 34A(0.20 g, 1.1 mmol, 92% yield) which was used directly in the next stepwithout further purification. LCMS=1.78 min [M+1]=192.1 (Method B).

Intermediate 34

To a stirred solution of Intermediate 34A (217 mg, 1.14 mmol) in THF (1mL) was added borane dimethylamine complex (1.14 mL, 1.14 mmol). Thereaction mixture was refluxed for 16 h. To this reaction mixture wasadded MeOH (1 mL), followed by 1N NaOH (1 mL) and the resulting solutionstirred at 70° C. for 2 h. The reaction mixture was cooled and washedwith saturated NaHCO₃. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated in vacuo to give Intermediate 34 (145mg, 0.82 mmol, 72.1% yield) which was used directly in the next step.LCMS=1.24 min [M+1]=178.1 (Method B).

Intermediates 35-37 were prepared according to the procedures describedin Intermediate 34 using the appropriate tetralin-1-one as the startingmaterial.

Intermediate No. Structure Name LC-MS [M + 1]/RT 35

5-methoxy-1,2,3,4- tetrahydronaphthalen-1-amine 178.1 (M + H)/1.24 min(Method B) 36

7-methoxy-1,2,3,4- tetrahydronaphthalen-1-amine 178.0 (M + H)/1.21 min(Method B) 37

6,7,8,9-tetrahydro-5H-benzo[7] annulen-5-amine 145.0 (M-NH₃ + H)/ 1.28min (Method B)

Intermediate 38. Ethyl 4-amino-3,4-dihydroquinoline-1(2H)-carboxylate

Intermediate 38A. (Ethyl4-(tert-butoxycarbonylamino)-3,4-dihydroquinoline-1(2H)-carboxylate

To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-4-ylcarbamate (65mg, 0.26 mmol) in DCM (1 mL) was added Na₂CO₃ (55.5 mg, 0.520 mmol),followed by ethyl carbonochloridate (0.028 mL, 0.29 mmol). The reactionmixture was stirred at rt for 2 h. The reaction mixture was diluted withDCM, washed with 1N HCl, dried over Na₂SO₄, filtered, and concentratedin vacuo to give Intermediate 38A (72 mg, 0.23 mmol, 86% yield).LCMS=1.97 min [M+Na]=342.9 (Method B).

Intermediate 38

To a solution of Intermediate 38A (30 mg, 0.094 mmol) in DCM (1 mL) wasadded 4N HCl in dioxane (0.023 mL, 0.094 mmol). The reaction was stirredat rt for 2 h. Organic solvents were evaporated under reduced pressureto give Intermediate 38 (20 mg, 0.091 mmol, 97% yield) which was used innext step without further purification. LCMS=1.19 min [M−NH₃+1]=204.1(Method B).

Intermediates 39-40 were prepared according to the procedures describedin Intermediate 38 using the appropriate coupling reagent as thestarting material.

Intermediate LC-MS No. Structure Name [M + 1]/RT 39

1-(methylsulfonyl)- 1,2,3,4- tetrahydroquinolin-4- amine 227.0 (M + H)/0.57 min (Method B) 40

7-methoxy-1,2,3,4- tetrahydronaphthalen-1- amine4-amino-N-(4-(trifluoromethyl)phenyl)- 3,4-dihydroquinoline- 1(2H)-carboxamide 318.9(M- NH₃ + H)/1.64 min (Method B)

Intermediate 41. (1R,3S)-3-(3,4-Dichlorophenyl)cyclopentanamine

and

Intermediate 42. (1S,3S)-3-(3,4-Dichlorophenyl)cyclopentanamine

Intermediate 41A. (S)-3-(3,4-Dichlorophenyl)cyclopentanone

A mixture of 3,4-dichlorophenylboronic acid (488 mg, 2.56 mmol),bis(norbornadiene)rhodium tetrafluoroborate (14.6 mg, 0.0390 mmol) andS-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.8 mg, 0.0410 mmol) indioxane (6.6 mL) was sparged with Ar three times and stirred at rt for 2h. To the reaction mixture was added water (1.015 mL) followed by theaddition of cyclopent-2-enone (200 mg, 2.44 mmol) and TEA (0.340 mL,2.44 mmol). The reaction mixture was stirred at room for 18 h. Thereaction mixture was diluted with DCM, washed with H₂O, dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography 40 g using hexanes/EtOAc (0-100% over 15 min, flow rate40 mL/min) to give Intermediate 41A (585 mg, 2.55 mmol, 100% yield) as ayellow oil. ¹H NMR (400 MHz, chloroform-d) δ ppm 1.86-2.02 (1H, m),2.18-2.38 (2H, m), 2.38-2.55 (2H, m), 2.67 (1H, dd, J=18.2, 7.4 Hz),3.28-3.49 (1H, m), 7.09 (1H, dd, J=8.0, 2.5 Hz), 7.34 (1H, d, J=1.8 Hz),7.41 (1H, d, J=8.3 Hz).

Intermediate 41B.N-((1R,3S)-3-(3,4-Dichlorophenyl)cyclopentyl)-2-methylpropane-2-sulfonamide

and

Intermediate 42B.N-((1S,3S)-3-(3,4-Dichlorophenyl)cyclopentyl)-2-methylpropane-2-sulfonamide

Intermediate 41B and 42B were prepared from Intermediate 41A andseparated in a similar procedure described in Intermediate 31A and 32A.LC-MS (ESI) 334.0. (M+H), RT=1.10 min (Method M).

Intermediate 41 and 42

Intermediate 41 and 42 were prepared from Intermediate 41B and 42B in asimilar procedure described in Intermediate 31 and 32.

Intermediate 41: LC-MS (ESI) 230.1 (M+H), RT=1.17 min (Method G).

Intermediate 42: LC-MS (ESI) 230.1 (M+H), RT=1.70 min (Method B).

Intermediates 43-44 were prepared according to the procedures describedin Intermediate 41 and 42 using the appropriate starting material.

Intermediate LC-MS No. Structure Name [M + 1]/RT 43

(1S,3R)-3-(3,4- dichlorophenyl) cyclopentanamine 230.1 (M + H)/1.68 min(Method B) 44

(1S,3R)-3-(3,4- dichlorophenyl) cyclopentanamine 230.1 (M + H)/1.71 min(Method B)

Intermediate 45. 3-(1-Benzyl-1H-pyrazol-4-yl)cyclohexanamine

Intermediate 45A. 3-(1-Benzyl-1H-pyrazol-4-yl)cyclohex-2-enone

To 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(406 mg, 1.43 mmol), 3-bromocyclohex-2-enone (200 mg, 1.14 mmol), andPd(PPh₃)₄ (132 mg, 0.114 mmol) in toluene (2 mL) was added 2M Na₂CO₃ (1mL). The reaction mixture was purged with nitrogen and heated at 110° C.for 16 h. The reaction was diluted with water (10 mL) and extracted DCM(3×15 mL), dried over Na₂SO₄ and purified by flash chromatography (24 gsilica gel) using hexanes/EtOAc (0-50% over 15 min, flow rate 35 mL/min)to isolate Intermediate 45A (160 mg, 0.634 mmol, 55.5% yield) as a tansolid. LC-MS (ESI) 253.0 (M+H), RT=1.70 min (Method B).

Intermediate 45

A mixture of Intermediate 45A (160 mg, 0.634 mmol) and ammonium formate(800 mg, 12.7 mmol) in MeOH (5 mL)/water (0.5 mL) was stirred at rt for45 min. The reaction was purged with nitrogen and treated with Pd/CDegussa wet type (100 mg, 0.634 mmol). After stirred for 16 h,additional amount of ammonium formate (800 mg, 12.7 mmol) was added.After 7 days, the reaction was filtered through Celite, concentrated,diluted in 1 N NaOH (50 mL), extracted with DCM (3×50 mL), dried overNa₂SO₄, concentrated, re-dissolved in methanol and purified using prepHPLC (0-100% B over 10 min, Column: PHENOMENEX® Luna Axia 5u C18 30×100mm; Solvent A: 10% ACN−90% H₂O-0.1% TFA; Solvent B: 90% ACN−10% H₂O-0.1%TFA, flow rate=40 mL/min) to isolate Intermediate 45 (130 mg, 0.509mmol, 80.0% yield) as a clear film. LC-MS (ESI) 256.1 (M+H), RT=1.43 min(Method B).

Intermediate 46.N-(4-(3-Aminocyclohexyl)phenyl)-4-methylbenzenesulfonamide

Intermediate 46 was prepared according to the procedures described inIntermediate 45 using the appropriate starting material. LC-MS (ESI)345.1 (M+H)/1.54 min (Method B).

Intermediate 47. 3-(6-Phenylbenzo[d]thiazol-2-yl)cyclopentanamine

To a suspension of(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (35.7mg, 0.156 mmol) in DMF (1 mL) was added DIPEA (0.082 mL, 0.47 mmol),3-((4-methoxybenzyl)thio)-[1,1′-biphenyl]-4-amine (50 mg, 0.16 mmol) andHATU (89 mg, 0.23 mmol). The reaction was stirred rt for 16 h. Themixture was concentrated, and the residue was dissolved in DCM andwashed with 1 N HCl and water. The organics were combined and dried overNa₂SO₄ and concentrated. TFA (1 mL) was added to the residue and thesolution was heated at 100° C. for 15 min in microwave. The reaction washeated at 60° C. for 16 h. The reaction was concentrated and dissolvedin ACN and purified by Prep HPLC (5-90% B over 12 min, Column:PHENOMENEX® Luna Axia 5 u C18 30×100 mm; Solvent A: 10% ACN−90% H₂O-0.1%TFA; Solvent B: 90% ACN−10% H₂O-0.1% TFA, flow rate=40 mL/min) to giveIntermediate 47 (22 mg, 48%) as a white solid. LC-MS (ESI) 295.0 (M+H),RT=1.86 min (Method B).

Intermediate 48. 1-(Pyridin-2-yl)pyrrolidin-3-amine

Intermediate 48A. tert-Butyl 1-(pyridin-2-yl)pyrrolidin-3-ylcarbamate

A mixture of 2-fluoropyridine (58.3 mg, 0.600 mmol), tert-butylpyrrolidin-3-ylcarbamate (55.9 mg, 0.300 mmol), and TEA (84.0 μL, 0.600mmol) in EtOH (1 mL) was heated at 120° C. for 30 min. The reaction wasconcentrated and the crude was purified by flash chromatography (12 gsilica gel) using hexanes/EtOAc (0-50% over 10 min, flow rate 30 mL/min)to give Intermediate 48A (15 mg, 0.057 mmol, 19% yield) as a whitesolid. LCMS=264.3 [M+1], RT=1.11 min (Method H). ¹H NMR (400 MHz,chloroform-d) δ ppm 8.15 (1H, dd, J=5.05, 1.01 Hz), 7.44 (1H, ddd,J=8.59, 6.95, 1.89 Hz), 6.55 (1H, dd, J=6.44, 5.18 Hz), 6.35 (1H, d,J=8.34 Hz), 4.74 (1H, br. s.), 4.35 (1H, br. s.), 3.71 (1H, dd, J=10.61,6.06 Hz), 3.46-3.64 (2H, m), 3.34 (1H, dd, J=10.61, 4.04 Hz), 2.27 (1H,td, J=13.20, 7.45 Hz), 1.96 (1H, td, J=12.51, 5.56 Hz), 1.45 (9H, s).

Intermediate 48

To a solution of Intermediate 48A (15 mg, 0.057 mmol) in DCM (0.2 mL)was added 4N HCl in dioxane (0.5 mL). The reaction was stirred at RT for2 h. The solvents were removed and the residue as Intermediate 48 wasdried and used directly in the next step. LCMS=164.1 [M+1], RT=0.24 min(Method B).

Example 1(R)-5-Amino-2,6-dioxo-N-(6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a 10-mL microwave reaction vial charged with5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (25 mg,0.15 mmol) in DMF (1 mL) was added EDC (35 mg, 0.18 mmol), HOBt (28 mg,0.18 mmol), and Intermediate 4 (35 mg, 0.15 mmol) followed by DIEA (0.13mL, 0.73 mmol). The resulting solution was stirred at rt for 14 h. Thereaction mixture was diluted with MeOH and purified by HPLC (0-75% Bover 12 min, Column: PHENOMENEX® Luna Axia 5u C18 30×100 mm; Solvent A:10% ACN−90% H₂O-0.1% TFA; Solvent B: 90% ACN−10% H₂O-0.1% TFA, flowrate=40 mL/min) to give Example 1 (20 mg, 0.056 mmol, 39% yield) as awhite solid. LCMS=355.3 [M+1], RT=1.76 min (Method B); Orthogonal HPLC(150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=7.40 min, 99.7%, Method A};Xbridge {RT=6.84 min, 99.8%, Method B}. ¹H NMR (400 MHz, Acetone-d₆) δppm 8.02 (1H, br. s.), 7.72 (1H, s), 7.57 (1H, d, J=7.83 Hz), 7.44-7.53(1H, m), 5.73 (2H, br. s.), 5.64 (1H, q, J=7.58 Hz), 3.08-3.22 (1H, m),2.93-3.06 (1H, m), 2.58-2.71 (1H, m, J=16.67, 8.15, 4.01, 4.01 Hz),2.08-2.19 (1H, m).

Examples 2-181 were prepared according the procedures described forExample 1 by using the appropriate intermediate amines and acids.

Examples 182-192 were prepared according the procedures described forExample 1 by using the appropriate intermediate amines and acids.

Example 193 Ethyl4-(5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3,4-dihydroquinoline-1(2H)-carboxylate(Enantiomer B)

The racemates from Example 25 were separated by using preparativechromatographic SFC to give enantiomer A (fast eluting peak, RT=5.70min) and enantiomer B as Example 193 (slow eluting peak, RT=6.33 min);Column: Regis Whelk-01(R, R), 250×4.6 mm ID, 5 μm; Flow rate: 3.0mL/min; Mobile Phase: 70/30 CO₂/Methanol; Detector Wavelength: 220 nm).SFC conditions are: Instrument: Berger MGII SFC; Column: RegisWhelk-01(R, R), 250×21 mm ID; Flow rate: 60 mL/min; Mobile Phase: 75/25CO₂/Methanol; Detector Wavelength: 240 nm; Sample Solution: 33 mg samplein 2 mL MeOH: Acetonitrile+40 μL DEA (˜16 mg/mL); collected fractions inmethanol. Example 193: LCMS=374 [M+1], RT=1.63 min (Method B);Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=6.31 min,88.8%, Method A}; Xbridge {RT=5.98 min, 86.7%, Method B}.

Examples 194-201 were obtained according to the procedures described inExample 193 using the appropriate racemic starting material.

Example 2025-Amino-N-(4-(3,4-difluorophenyl)cyclohex-3-enyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 202A5-Amino-N-(cis-4-(3,4-difluorophenyl)-4-hydroxycyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 202A was prepared according the procedures described for Example1 by using Intermediate 10. LCMS=381.5 [M+1] RT=1.77 min (Method E);Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=5.48 min,96.1%, Method A}; Xbridge {RT=5.10 min, 95.6%, Method B).

Example 202

To a solution of Example 202A (10 mg, 0.026 mmol) in DCM (0.50 mL) wasadded TFA (0.20 mL, 2.6 mmol). The resulting solution was stirred at rtfor 30 min. The reaction was concentrated and titrated with MeOH to giveExample 202 as a white solid (4.5 mg, 0.012 mmol, 47% yield). LCMS=363.1[M+1] RT=2.47 min (Method G); Orthogonal HPLC (150×4.6 mm 3.5 um, 254nm): Sunfire {RT=7.73 min, 85.8%, Method A}; Xbridge {RT=7.18 min,84.7%, Method B). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.47 (1H, br. s.),9.91 (1H, br. s.), 8.02 (1H, d, J=6.57 Hz), 7.49 (1H, dd, J=11.37, 8.84Hz), 7.32-7.43 (1H, m), 7.29 (1H, br. s.), 6.17 (1H, br. s.), 5.95 (2H,br. s.), 4.00 (1H, br. s.), 2.52-2.67 (2H, m), 2.17 (1H, dd, J=15.79,7.96 Hz), 1.89-2.09 (1H, m), 1.59-1.84 (1H, m), 1.15-1.36 (1H, m).

Example 2035-Amino-3-(3-fluoro-5-(trifluoromethyl)phenyl)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a solution of Example 3 (25 mg, 0.076 mmol),3-fluoro-5(trifluoromethyl)phenylboronic acid (32 mg, 0.15 mmol) in MeOH(3045 μL) and water (761 μL) was added Cu(OAc)₂ (14 mg, 0.076 mmol)followed by addition of TMEDA (23.0 μL, 0.15 mmol). The reaction mixturewas stirred at rt for 1.5 h. The reaction was concentrated and purifiedby HPLC (5-90% B over 12 min, Column: PHENOMENEX® Luna Axia 5u C1830×100 mm; Solvent A: 10% ACN−90% H₂O-0.1% TFA; Solvent B: 90% ACN-10%H₂O-0.1% TFA, flow rate=40 mL/min) to give Example 203 (5.0 mg, 10 mol,13% yield) as a white solid. LCMS=490.9 [M+1], RT=2.16 min (Method B);Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=9.95 min, 100%,Method A}; Xbridge {RT=8.93 min, 100%, Method B}.

Example 204 was prepared according the procedures described for Example203 by using the appropriate intermediate boronic acid.

Example 2055-(4-Fluorobenzylamino)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 205A2,6-Dioxo-N-((1s,4s)-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a 10 mL microwave reaction vial charged with2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (3.00 g, 19.2mmol) and DMF (10 mL) was added EDC (4.05 g, 21.1 mmol), HOBt (3.24 g,21.1 mmol), and Intermediate 1, HCl salt (4.07 g, 19.2 mmol) followed byDIEA (10.1 mL, 57.7 mmol). The resulting solution was stirred at rt for16 h. The reaction mixture then was heated at 55° C. for 2 h. Thereaction was diluted with water and extracted with DCM (3×). Theorganics were combined and dried over MgSO₄ and concentrated. The crudewas purified by flash chromatography (0-10% MeOH in DCM) to give Example205A (4.5 g, 14 mmol, 75% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) d ppm 11.23 (1H, br. s.), 10.86 (1H, br. s.), 8.48 (1H, d,J=7.15 Hz), 7.23-7.38 (4H, m), 7.13-7.23 (1H, m), 5.96-6.11 (1H, m),4.08 (1H, ddd, J=7.02, 3.44, 3.30 Hz), 2.55-2.66 (1H, m), 1.77-1.97 (4H,m), 1.56-1.75 (4H, m). LCMS=314.1 [M+1], RT=3.44 min (Method A).

Example 205B5-Bromo-2,6-dioxo-N-((1s,4s)-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a vigorously stirred solution of Example 205A (0.27 g, 0.86 mmol) inacetic acid (15 mL) was added bromine (0.044 mL, 0.86 mmol) in aceticacid (5 mL) dropwise slowly over a 1 h period. The reaction was stirredat rt for 16 h. The reaction was diluted with water and filtered andrinsed with water to give Example 205B (289 mg, 0.737 mmol, 86.0% yield)as a white solid. LCMS=391.9 [M+1], 393.9 [M+3], RT=3.44 min (Method A).

Example 205

A mixture of (4-fluorophenyl)methanamine (63.8 mg, 0.510 mmol) andExample 205B (10 mg, 0.025 mmol) in dioxane (0.5 mL) was microwaved at120° C. for 2 h. The reaction mixture was concentrated and purified byPrep-HPLC (0-100% MeOH/H₂O with 0.1% TFA as modifier over 10 min).Product was eluted at a retention time of 11.41 min, collected andconcentrated to give Example 205 (6.0 mg, 0.014 mmol, 54% yield) as acolorless oil. LCMS=437.0 [M+1] RT=2.19 min (Method B); Orthogonal HPLC(150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=9.90 min, 100%, Method A};Xbridge {RT=9.06 min, 100%, Method B).

Examples 206-237 were prepared according the procedures described forExample 205 by using the appropriate intermediate amines and acids undermicrowave heating from 120 to 200° C. either neat or in solvents such asethanol, dioxane, or ethylene glycol.

Example 238Hydroxy-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 238A Ethyl5-(benzyloxy)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate

A solution of ethyl 2-(benzyloxy)acetate (24.9 g, 128 mmol) and diethyloxalate (20.9 mL, 154 mmol) in THF (220 mL) was cooled to −78° C. underargon. Lithium bis(trimethylsilyl)amide (192 mL, 192 mmol) was addeddropwise to this solution and the resulting mixture was stirred at −78°C. for 4 h. The reaction mixture was concentrated and the brown oilyresidue was dissolved in EtOH (450 mL). 2-Methyl-2-thiopseudoureasulfate (26.5 g, 141 mmol) was added and the mixture was stirred at 70°C. for 24 h. The reaction mixture was allowed to cool to rt andconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and 1N HCl. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting brown oil was purifiedby flash chromatography eluting with EtOAc/hexanes (0-50%) to give ayellow residue that was crystallized from hot EtOAc/hexanes (1:4). Theresulting white solid was collected by filtration to give Example 238A(6.01 g, 18.8 mmol, 14.6% yield). LC-MS (ESI) 321.2 (M+H), retentiontime=2.21 min (Method B). ¹H NMR (300 MHz, CDCl₃) δ: 12.03 (1H, bs),7.45 (2H, dd, J=7.9, 1.6 Hz), 7.36-7.29 (3H, m), 5.22 (2H, s), 4.31 (2H,q, J=7.2 Hz), 2.56 (3H, s), 1.29 (3H, q, J=7.1 Hz).

Example 238B5-(Benzyloxy)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid

Example 238A (99 mg, 0.31 mmol) was stirred in ethanol (3 mL) at rt. 1 NNaOH (1.5 mL) was added. The reaction was stirred at 50° C. for 1 h.After cooling, the mixture was concentrated under reduced pressure andconcentrated HCl was then added dropwise to the remaining mixture. Theresulting white precipitate was filtered, and rinsed with H₂O, and thendried in vacuo to give Example 238B (70 mg, 0.24 mmol, 77% yield) aswhite solids. LC-MS (ESI) 292.9 (M+H), retention time=1.52 min (MethodB).

Example 238C5-(Benzyloxy)-2-(methylthio)-6-oxo-N-(cis-4-phenylcyclohexyl)-1,6-dihydropyrimidine-4-carboxamide

To a 1-dram vial charged with Example 238B (65 mg, 0.22 mmol),cis-4-phenylcyclohexanamine hydrochloride (57 mg, 0.27 mmol) and DMF(0.5 mL) was added EDC (53 mg, 0.28 mmol), HOBt (43 mg, 0.28 mmol)followed by DIEA (0.19 mL, 1.1 mmol). The resulting mixture was stirredat rt for 16 h. EtOAc was added. The solution was washed with H₂O,brine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was dissolved in CH₂Cl₂ and purified by silica gelflash column chromatography (0-100% EtOAc/hexanes) to give Example 238C(70 mg, 0.16 mmol, 70% yield) as white solids. LC-MS (ESI) 449.9 (M+H),retention time=2.26 min (Method B).

Example 238D5-Benzyloxy-2-methanesulfonyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylicacid (cis-4-phenyl-cyclohexyl)-amide

Example 238C (70 mg, 0.16 mmol) was stirred in CH₂Cl₂ (3 mL) at rt for16 h. Additional CH₂Cl₂(10 mL) was added. The reaction mixture waswashed with aqueous Na₂CO₃, aqueous Na₂SO₃, H₂O, and then brine, driedover MgSO₄, filtered and concentrated to give Example 238D which wasused directly in the next step without further purification. LC-MS (ESI)481.9 (M+H), retention time=2.18 min (Method B).

Example 238E5-(Benzyloxy)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 238D (75 mg, 0.16 mmol) was dissolved in dioxane (3 mL). 1N NaOH(1 mL, 1.0 mmol) was added. The resulting solution was stirred at rt for1 h. The reaction mixture was concentrated and made acidic by theaddition of 1 N HCl. The resulting solution was concentrated underreduced pressure and the residue dissolved in MeOH, then purified byHPLC(CH₃CN/H₂O/TFA) to give Example 238E (23 mg, 0.060 mmol, 35% yield)as a white solid. LC-MS (ESI) 419.9 (M+H), retention time=2.19 min(Method B). ¹H NMR (400 MHz, acetone) δ ppm 10.37 (1H, br. s.), 8.34(1H, br. s.), 7.50-7.65 (2H, m), 7.32-7.44 (3H, m), 7.22-7.31 (2H, m),7.14-7.22 (1H, m), 7.07 (2H, d, J=7.1 Hz), 5.37 (2H, s), 4.17 (1H, dt,J=7.1, 3.6 Hz), 2.45-2.65 (1H, m), 1.77-1.89 (2H, m), 1.71 (2H, tt,J=13.4, 3.8 Hz), 1.60 (2H, d, J=13.9 Hz), 1.26-1.48 (2H, m).

Example 238

Example 238E (18 mg, 0.043 mmol) was stirred in CH₂Cl₂(2.5 mL) and TFA(2.5 mL) under microwave irradiation at 120° C. for 20 min. The vial wasthen heated in an oil bath at 50° C. for 16 h. After cooling, thereaction mixture was concentrated under reduced pressure, dissolved inMeOH and purified by HPLC(CH₃CN/H₂O/TFA) to give Example 238 (5.0 mg,0.020 mmol, 35% yield) as a white solid. LC-MS (ESI) 330.1 (M+H),retention time=1.93 min (Method B). Orthogonal HPLC (150×4.6 mm 3.5 um,254 nm): RT=6.69 min, 100% (Method A); RT=6.21 min, 100% (Method B). ¹HNMR (400 MHz, MeOD) δ ppm 7.29-7.14 (5H, m), 4.31 (1H, m), 2.64 (1H, m),1.98-1.94 (2H, m), 1.85-1.78 (4H, m), 1.74-1.67 (2H, m).

Example 2391-Ethyl-5-hydroxy-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

and

Example 2403-Benzyl-1-ethyl-5-hydroxy-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 239A5-(Benzyloxy)-6-ethoxy-2-(methylthio)-N-(cis-4-phenylcyclohexyl)pyrimidine-4-carboxamide

and

Example 239B5-(Benzyloxy)-1-ethyl-2-(methylthio)-6-oxo-N-(cis-4-phenylcyclohexyl)-1,6-dihydropyrimidine-4-carboxamide

To a solution of Example 238C (75 mg, 0.17 mmol) in DMF (1 mL) was addedcesium carbonate (82 mg, 0.25 mmol) and iodoethane (0.013 mL, 0.17 mmol)dropwise. The reaction was stirred at rt for 14 h. The reaction mixturewas diluted with water and extracted with EtOAc (2×). The combinedorganic layers were dried over Na₂SO₄ and concentrated and purified byflash chromatography (0-30% EtOAc/hexanes over 10 min then 30-100% over3 min on a 12 g silica gel column) to give Example 239A (faster eluant,27 mg, 0.057 mmol, 34% yield) as a white solid and Example 239B (slowereluant, 27 mg, 0.057 mmol, 34% yield) as a colorless oil. Example 239A:LC-MS (ESI) 478.1 (M+H), retention time=4.56 min (Method A). ¹H NMR (400MHz, chloroform-d) δ ppm 8.01 (1H, d, J=8.24 Hz), 7.53 (2H, d, J=7.15Hz), 7.26-7.37 (5H, m), 7.20 (1H, br. s.), 7.18 (2H, d, J=3.85 Hz), 5.10(2H, s), 4.46 (2H, q, J=7.15 Hz), 4.35 (1H, dd, J=7.97, 3.57 Hz),2.57-2.66 (1H, m), 2.55 (3H, s), 1.97 (2H, d, J=13.19 Hz), 1.69-1.87(4H, m), 1.53-1.66 (2H, m), 1.42 (3H, t, J=6.87 Hz). Example 239B: LC-MS(ESI) 478.1 (M+H), retention time=4.35 min (Method A). ¹H NMR (400 MHz,chloroform-d) δ ppm 7.86 (1H, d, J=7.70 Hz), 7.56 (2H, d, J=6.05 Hz),7.30 (5H, m), 7.18-7.24 (1H, m), 7.14 (2H, d, J=7.15 Hz), 5.28 (2H, s),4.32-4.40 (1H, m), 4.15 (2H, q, J=7.15 Hz), 2.65 (3H, s), 2.54-2.63 (1H,m), 1.92 (2H, d, J=11.54 Hz), 1.67-1.83 (4H, m), 1.42-1.58 (2H, m), 1.37(3H, t, J=7.15 Hz).

Example 239C5-(Benzyloxy)-1-ethyl-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

A mixture of Example 239B (63 mg, 0.13 mmol) and mCPBA (114 mg, 0.462mmol) was stirred in CH₂Cl₂(1.5 mL) at rt for 14 h. Dioxane (1 mL) and2.5 N NaOH (1 mL) was added and the resulting reaction mixture wasstirred at rt for 1.5 h. Saturated Na₂S₂O₃ was added and the reactionmixture stirred for 5 min. A suspension was obtained and filtered. Thefilter cake was washed with water. The white solid was further driedunder reduced vacuum to give Example 239C (47 mg, 0.11 mmol, 80% yield).LC-MS (ESI) 448.1 (M+H), retention time=2.33 min (Method B).

Example 239 and Example 240

Example 239C (18 mg, 0.040 mmol) was stirred in CH₂Cl₂(2.5 mL) and TFA(2.5 mL) under microwave irradiation at 120° C. for 30 min. The vial wasthen heated in an oil bath at 50° C. for 14 h. After cooling, themixture was concentrated and re-dissolved in MeOH and purified by prepHPLC(CH₃CN/H₂O/TFA) to give Example 239 (8.0 mg, 0.022 mmol, 56% yield)and Example 240 (2.0 mg, 4.5 mol, 11% yield).

Example 239: LC-MS (ESI) 358.1 (M+H), retention time=2.12 min (MethodB). Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=8.46 min,100%, Method A}; Xbridge {RT=7.56 min, 100%, Method B).

Example 240: LC-MS (ESI) 448.1 (M+H), retention time=2.39 min (MethodB). Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=10.85 min,93.1%, Method A}; Xbridge {RT=9.48 min, 100%, Method B).

Example 2415-Hydroxy-3-methyl-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 241A5-(Benzyloxy)-6-ethoxy-2-oxo-N-(cis-4-phenylcyclohexyl)-2,3-dihydropyrimidine-4-carboxamide

A mixture of Example 239A (75 mg, 0.16 mmol) and mCPBA (135 mg, 0.550mmol) was stirred in CH₂Cl₂(3 mL) at rt for 14 h. To the reaction wasadded sodium hydroxide (1 mL, 1 mmol) and the resulting solution stirredfor 2 h. Additional CH₂Cl₂ (10 mL) was added. The reaction mixture waswashed with aqueous Na₂CO₃, aqueous Na₂SO₃, H₂O and brine, then driedover MgSO₄, filtered and concentrated to give Example 241A (9.0 mg,0.020 mmol, 13% yield). LC-MS (ESI) 448.2 (M+H), retention time=2.28 min(Method B).

Example 241B5-(Benzyloxy)-6-ethoxy-3-methyl-2-oxo-N-(cis-4-phenylcyclohexyl)-2,3-dihydropyrimidine-4-carboxamide

To a solution of Example 241A (15 mg, 0.034 mmol) in DMF (1 mL) wasadded iodomethane (2.0 μl, 0.034 mmol) dropwise. The reaction wasstirred at rt for 14 h. The reaction mixture was diluted with water andextracted with EtOAc (2×). The combined organic layers were dried overNa₂SO₄ and concentrated and purified by flash chromatography (10%MeOH/DCM over 10 min on silica gel) followed by prep HPLC(ACN/water/TFA) to give Example 241B (6.0 mg, 0.013 mmol, 39% yield) asa white solid. LC-MS (ESI) 462.2 (M+H), retention time=2.23 min (MethodB). ¹H NMR (500 MHz, chloroform-d) δ ppm 7.31-7.40 (5H, m), 7.25 (2H, d,J=7.43 Hz), 7.16-7.20 (1H, m), 7.13 (2H, d, J=6.88 Hz), 7.00 (1H, d,J=6.60 Hz), 4.90 (2H, s), 4.44 (2H, q, J=6.97 Hz), 4.33 (1H, ddd,J=7.22, 3.51, 3.30 Hz), 3.44 (3H, s), 2.56 (1H, tt, J=11.14, 3.44 Hz),1.93 (2H, d, J=2.20 Hz), 1.69-1.80 (5H, m, J=13.38, 13.38, 13.14, 3.58Hz), 1.66 (2H, dd, J=13.62, 2.89 Hz), 1.36 (3H, t, J=7.02 Hz).

Example 241

Example 241B (6.0 mg, 0.013 mmol) was stirred in CH₂Cl₂ (2.5 mL) and TFA(2.5 mL) under microwave irradiation at 120° C. for 30 min. Aftercooling, the mixture was concentrated and redissolved in MeOH andpurified by prep HPLC (CH₃CN/H₂O/TFA) to give Example 241 (2.0 mg, 5.8μmol, 49% yield). LC-MS (ESI) 344.1 (M+H), retention time=1.82 min(Method B). PHENOMENEX® Luna C18; 30×2.0 mm; 2 min Grad}; OrthogonalHPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=8.57 min, 100%, Method A};Xbridge {RT=6.11 min, 100%, Method B). ¹H NMR (400 MHz, acetone-d₆) δppm 7.07-7.31 (5H, m), 4.30 (1H, br. s.), 3.27 (3H, s), 2.54-2.72 (1H,m, J=11.68, 11.68, 3.85, 3.57 Hz), 1.99-2.03 (2H, m), 1.86-1.97 (2H, m),1.69-1.84 (4H, m).

Examples 242-266 were prepared according the procedures described forExamples 239-241 by using the appropriate intermediate amines and acids.

Example 2672-(5-Hydroxy-2,6-dioxo-4-((cis-4-phenylcyclohexyl)carbamoyl)-2,3-dihydropyrimidin-1(6H)-yl)aceticacid

Example 267A tert-Butyl5-(benzyloxy)-1-(2-methoxy-2-oxoethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate

tert-Butyl5-(benzyloxy)-2-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (300mg, 0.903 mmol) and sodium hydride (36.1 mg, 0.903 mmol) were stirred inanhydrous DMF (903 μl) at 0° C. under argon for 30 min. Methyl2-bromoacetate (83 μl 0.90 mmol) was added and the mixture was stirredat rt for 3 h. The reaction was carefully quenched with water at 0° C.The reaction mixture was extracted with EtOAc (3×). The combined organiclayers were washed with water, brine, dried over Na₂SO₄, concentratedand purified by flash chromatography (hexanes/EtOAc, eluted at ca. 30%EtOAc) to give tert-butyl5-(benzyloxy)-2-methoxy-6-(2-methoxy-2-oxoethoxy)pyrimidine-4-carboxylate(109 mg, 0.270 mmol, 29.9% yield) as a colorless oil and Example 267A(117 mg, 0.289 mmol, 32.1% yield) as a colorless oil. ¹H NMR (500 MHz,chloroform-d) δ 7.49-7.44 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.27 (m, 1H),5.12 (s, 2H), 4.74 (s, 2H), 4.00 (s, 3H), 3.75 (s, 3H), 1.51 (s, 9H).LC-MS (ESI) 349.0 (M+H-t-Bu), retention time=2.07 min (Method B).

Example 267B5-(Benzyloxy)-1-(2-methoxy-2-oxoethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylicacid

To a solution of Example 267A (117 mg, 0.289 mmol) in MeOH (2 mL) wasadded concentrated HCl (2.00 mL, 65.8 mmol). The reaction was stirred atrt for 48 h. The reaction was concentrated and filtered and rinsed withwater. The filter cake was collected and dried under reduced vacuum togive Example 267B (97.0 mg, 0.290 mmol, 100% yield) as a white solid.LC-MS (ESI) 357.0 (M+Na), retention time=1.53 min (Method B).

Example 267C Methyl2-(5-(benzyloxy)-2,6-dioxo-4-((cis-4-phenylcyclohexyl)carbamoyl)-2,3-dihydropyrimidin-1(6H)-yl)acetate

To a vial charged with Example 267B (34.8 mg, 0.165 mmol) in DMF (0.5mL) was added EDC (35.8 mg, 0.187 mmol), HOBt (28.6 mg, 0.187 mmol)followed by DIEA (0.131 mL, 0.748 mmol) and Intermediate 9 (34.8 mg,0.165 mmol). The resulting mixture was stirred at rt for 16 h. Themixture was diluted with EtOAc and washed with H₂O, brine, dried overMgSO₄, filtered and concentrated. The residue was dissolved in CH₂Cl₂and purified by flash chromatography (0-100% EtOAc in hexanes) to giveExample 267C (10 mg, 0.020 mmol, 14% yield) as a white solid. LC-MS(ESI) 492.1 (M+H), retention time=2.26 min (Method B).

Example 267D2-(5-(Benzyloxy)-2,6-dioxo-4-((cis-4-phenylcyclohexyl)carbamoyl)-2,3-dihydropyrimidin-1(6H)-yl)aceticacid

To Example 267C (40 mg, 0.081 mmol) in MeOH (1 mL) and THF (1 mL) wasadded LiOH (3.90 mg, 0.163 mmol) and the reaction was stirred for 3 h.The reaction was concentrated and dried under reduced vacuum to giveExample 267D as a white solid. LC-MS (ESI) 478.2 (M+H), retentiontime=2.18 min (Method B).

Example 267

To Example 267D (10 mg, 0.021 mmol) in CH₂Cl₂(1 mL) was added TFA (0.2mL). The resulting solution was heated at 120° C. for 15 min inmicrowave. The reaction was concentrated and dissolved in MeOH andpurified by Prep HPLC (10-100% B over 10 min, ACN/H₂O/TFA) to giveExample 267 (4.00 mg, 9.91 μmol, 47.3% yield) as a white solid. ¹H NMR(500 MHz, MeOD) δ 7.32-7.23 (m, 4H), 7.20-7.14 (m, 1H), 4.66 (s, 2H),4.34 (t, J=3.0 Hz, 1H), 2.71-2.59 (m, 1H), 2.03-1.94 (m, 2H), 1.89-1.78(m, 4H), 1.75-1.63 (m, 2H). LCMS=388.1 [M+H] RT=1.91 min (Method B).Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=9.33 min, %,Method A}; Xbridge {RT=7.60 min, 96.0%, Method B).

Example 2685-Hydroxy-2,6-dioxo-1-(2-oxo-2-((cis-4-phenylcyclohexyl)amino)ethyl)-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 268A5-(Benzyloxy)-2,6-dioxo-1-(2-oxo-2-((cis-4-phenylcyclohexyl)amino)ethyl)-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a vial charged with Intermediate 1 (18 mg, 0.084 mmol) and Example267D (20 mg, 0.042 mmol) in dioxane (0.5 mL) was added DIEA (0.037 mL,0.21 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (0.037 mL, 0.063 mmol). The resulting mixture was stirredat rt for 1 h. DMF (0.3 mL) was added and the reaction was heated at 50°C. for 3 h then at rt for 3 days. The mixture was diluted with EtOAc andwashed with H₂O, brine, dried over MgSO₄, filtered and concentrated. Theresidue was dissolved in CH₂Cl₂ and purified by flash chromatography(0-100% EtOAc/hexanes) to give Example 268A (10 mg, 0.016 mmol, 38%yield) as a white solid. LC-MS (ESI) 635.3 (M+H), retention time=2.47min (Method B).

Example 268

To Example 268A (10 mg, 0.016 mmol) in CH₂Cl₂(1 mL) was added TFA (0.2mL). The resulting solution was heated at 120° C. for 15 min inmicrowave. The reaction was concentrated and dissolved in MeOH andpurified by Prep HPLC (10-100% B over 10 min, ACN/H₂O/0.1% TFA) to giveExample 268 (4.00 mg, 7.27 mol, 46.2% yield) as a white solid. ¹H NMR(500 MHz, MeOD) δ 8.26 (d, J=6.9 Hz, 1H), 7.38-7.21 (m, 9H), 7.21-7.08(m, 2H), 4.69 (s, 2H), 4.38-4.26 (m, 1H), 4.20-4.02 (m, 1H), 2.73-2.50(m, 2H), 2.03-1.95 (m, 2H), 1.95-1.88 (m, 2H), 1.88-1.76 (m, 6H),1.76-1.61 (m, 6H). LCMS=545.3 [M+H] RT=2.29 min (Method B). OrthogonalHPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=10.68 min, 99.0%, MethodA}; Xbridge {RT=10.18 min, 99.3%, Method B).

Example 2695-Hydroxy-1-(2-hydroxyethyl)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 269A5-(Benzyloxy)-1-(2-hydroxyethyl)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a solution of Example 267C (25 mg, 0.051 mmol) in THF (1 mL) at 0° C.was added lithium borohydride (2M in THF) (38 μl, 0.076 mmol) slowly.The reaction was slowly warmed to room temperature where it was stirredat for 16 h. The mixture was slowly quenched with water. The organiclayer was separated and the aqueous phase was extracted with EtOAc. Thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.The crude material was purified by flash chromatography over 4 g ofsilica gel (20 min gradient with 0-100% ethyl acetate in hexanes) toafford Example 269A (22 mg, 0.047 mmol, 93% yield) as a white foam.LCMS=464.1 [M+H] RT=2.19 min (Method B).

Example 269

To a solution of Example 269A (22 mg, 0.047 mmol) in CH₂Cl₂(1 mL) wasadded Pd/C (5.1 mg, 0.047 mmol). The reaction mixture was stirred underH₂ for 2 h. The reaction mixture was filtered through the Celite andrinsed with MeOH. The filtrate was concentrated. The desired product waspurified by prep HPLC using a 10 minutes gradient from 0 to 100% B(Column: PHENOMENEX® Luna Axia 100×20 mm 5u (10 min gradient). SolventA: 10% ACN−90% H₂O-0.1% TFA. Solvent B: 90% ACN−10% H₂O-0.1% TFA) togive Example 269 (5.0 mg, 0.013 mmol, 27% yield). LCMS=1.92 minutes[M+H]=374.0 (Method B). Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm):Sunfire {RT=7.31 min, 96.2%, Method A}; Xbridge {RT=6.93 min, 100%,Method B}. ¹H NMR (500 MHz, MeOD) δ 7.31-7.22 (m, 4H), 7.19-7.13 (m,1H), 4.37-4.27 (m, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.76 (t, J=6.1 Hz, 2H),2.72-2.57 (m, 1H), 2.04-1.91 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.60 (m,2H).

Example 2705-Hydroxy-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1-(3-phenylpropyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

Example 270 was prepared in similar procedure described in Example 267.LC-MS (ESI) 448.2 (M+H), retention time=2.32 min (Method B).

Example 2715-Hydroxy-2,6-dioxo-N-((1R,3S)-3-phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

To a reaction vial charged with Example 75 (10 mg, 0.032 mmol) indioxane (0.8 mL) was added 1 N hydrogen chloride (0.795 mL, 0.795 mmol).The resulting mixture was stirred at 100° C. for 2 h. The reaction wascooled down to rt and the solvents were removed. The residue wasdissolved in MeOH and DIEA (2 drops) and purified by Prep HPLC (0-100% Bover 10 min, ACN/H₂O/0.1% TFA) to give Example 271 (9.0 mg, 0.028 mmol,87% yield) as a white solid. LCMS=316.2 [M+H] RT=1.91 min (Method H);Orthogonal HPLC (150×4.6 mm 3.5 um, 254 nm): Sunfire {RT=6.82 min,98.8%, Method A}; Xbridge {RT=6.51 min, 96.8%, Method B).

Examples 272-298 were prepared according the procedures described forExample 271 by using the appropriate intermediates.

Example 299(S)-5-(2-Hydroxyethoxy)-2,6-dioxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide

(S)-5-Fluoro-2,6-dioxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide(45.0 mg, 0.148 mmol) and potassium trimethylsilanolate (148 mg, 1.15mmol) were stirred in diglyme (0.1 mL) at 120° C. for 16 h. Aftercooling, the reaction was quenched by adding 1 N HCl while cooling in anice water bath. The mixture was purified by RP HPLC to give Example 299(7.0 mg, 0.019 mmol, 13% yield). LC-MS (ESI) 346.2 (M+H), retentiontime=2.83 min (Method A).

The analytical data (mass, retention time, and conditions of LC-MS) ofExamples 2-181, 182-192, 194-201, 204, 206-237, 242-266, and 272-298 arelisted in Table 2.

TABLE 2 Ex. LC-MS No. Structure Name [M + 1]/RT Purity (%) 2

5-amino-2,6-dioxo-N-(4- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 329.0/1.90 min (Method B) RT = 7.50min, 99.6% (Method A) RT = 6.99 min, 98.6% (Method B) 3

5-amino-2,6-dioxo-N-(cis-4- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 329.3/1.86 min (Method B) RT = 7.50min, 100% (Method A) RT = 6.98 min, 100% (Method B) 4

5-amino-N-(cis-4-(4-fluorophenyl)-4- methoxycyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 377.3/1.77 min (Method B) RT= 6.82 min, 99.2% (Method A) RT = 6.31 min, 99.0% (Method B) 5

(R)-5-amino-N-(4,6-dichloro-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 355.0/2.49 min (Method G) RT= 8.10 min, 98.8% (Method A) RT = 7.48 min, 96.6% (Method B) 6

5-amino-2,6-dioxo-N-(4-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 377.1/2.03 min (Method B) RT= 8.52 min, 100% (Method A) RT = 7.98 min, 100% (Method B) 7

5-amino-N-(cis-4-cyano-4-(3,4- dichlorophenyl)cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.9/2.05 min (MethodB) RT = 8.29 min, 98.1% (Method A) RT = 7.80 min, 99.2% (Method B) 8

5-amino-N-(1-benzyl-2,3-dihydro- 1H-inden-2-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 377.1/2.03 min (Method F) 98.2% 9

(R)-5-amino-N-(2,3-dihydro-1H- inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 287.1/1.32 min (Method F) 97.7% 10

(S)-5-amino-2,6-dioxo-N-(1,2,3,4- tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 301.1/1.52 min (Method F) 97.4% 11

5-amino-N-(6-methoxy-2,3-dihydro- 1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 317.0/1.43 min (Method F) 100% 12

(1R,3S)-methyl 3-(5-amino-2,6- dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-2,3-dihydro-1H- indene-1-carboxylate 345.1/1.34 min (MethodF) 100% 13

(R)-5-amino-2,6-dioxo-N-(1,2,3,4- tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 301.1/1.51 min (Method F) 100% 14

(R)-5-amino-2,6-dioxo-N-(4- (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 355.1/2.36 min(Method G) RT = 7.62 min, 98.2% (Method A) RT = 7.07 min, 99.2% (MethodB) 15

(S)-5-amino-2,6-dioxo-N-(6- (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 355.1/2.33 min(Method G) RT = 7.52 min, 98.0% (Method A) RT = 6.96 min, 98.9% (MethodB) 16

tert-butyl 4-(5-amino-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3,4-dihydroquinoline- 1(2H)-carboxylate 345.9 (M-tBu +H)/1.91 min (Method B) RT = 4.12 min, 97.1% (Method A) RT = 4.83 min,98.8% (Method B) 17

5-amino-N-(7-methoxy-2- methylchroman-4-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 347.1/1.92 min (Method G) RT= 6.34 min, 97.6% (Method A) RT = 5.99 min, 99.3% (Method B) 18

  (1:1 cis isomers) 5-amino-2,6-dioxo-N-(cis-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide363.3/1.97 min (Method B) RT = 8.29 min, 97.7% (Method A) RT = 7.82 min,99.0% (Method B) 19

5-amino-2,6-dioxo-N-((1R,4R)-4- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 376/2.10 min (MethodB) RT = 8.62 min, 100% (Method A) RT = 8.10 min, 100% (Method B) 20

5-amino-2,6-dioxo-N-((1R,4S)-4- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 399.3/2.01 min (M +Na, Method H) RT = 8.50 min, 100% (Method A) RT = 8.04 min, 100% (MethodB) 21

methyl 2-((1S,2R,4S)-4-(5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamido)-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate 449.3/2.56 min (Method G) RT = 8.50min, 98.7% (Method A) RT = 8.05 min, 98% (Method B) 22

5-amino-2,6-dioxo-N-(6-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide399.1/1.91 min (Method A) RT = 8.17 min, 97.9% (Method A) RT = 7.73 min,97.6% (Method B) 23

(1R,2R,4R)-methyl 4-(5-amino-2,6- dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-1-phenyl-1,2,3,4- tetrahydronaphthalene-2-carboxylate435.1/1.82 min (Method B) RT = 8.17 min, 97.9% (Method A) RT = 7.73 min,96.6% (Method B) 24

5-amino-N-(1-(methylsulfonyl)- 1,2,3,4-tetrahydroquinolin-4-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 380.1/1.67 min (MethodB) RT = 5.48 min, 94.5% (Method A) RT = 5.31 min, 96.8% (Method B) 25

ethyl 4-(5-amino-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamido)-3,4-dihydroqiiinoline- 1(2H)-carboxylate 378/1.14 min(Method B) RT = 6.28 min, 97.4% (Method A) RT = 5.93 min, 98.9% (MethodB) 26

4-(5-amino-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4- carboxamido)-N-(4-(trifluoromethyl)phenyl)-3,4- dihydroquinoline-1(2H)-carboxamide449.1/1.43 min (Method B) RT = 8.37 min, 94.3% (Method A) RT = 7.84 min,92.5% (Method B) 27

(R)-5-amino-2,6-dioxo-N-(5- (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 355.1/2.39 min(Method B) RT = 7.04 min, 100% (Method A) RT = 6.39 min, 99.5% (MethodB) 28

5-amino-2,6-dioxo-N-((1S,3S)-3- phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 363.3/3.53 min (Method J) RT= 7.93 min, 96.8% (Method A) RT = 7.21 min, 96.9% (Method B) 29

5-amino-2,6-dioxo-N-((1R,3S)-3- phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 363.3/3.53 min (Method J) RT= 7.93 min, 98.8% (Method A) RT = 7.18 min, 99.1% (Method B) 30

5-amino-2,6-dioxo-N-(cis-4-(3- (trifluoromethyl)phenyl)cyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 397/1.99 min (Method B) RT =8.82 min, 94.4% (Method A) RT = 8.10 min, 95.0% (Method B) 31

5-amino-N-(6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 331/1.66 min (Method B) RT =6.55 min, 95.3% (Method A) RT = 6.16 min, 99.3% (Method B) 32

5-amino-N-(chroman-4-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 303/1.46 min (Method B) RT = 5.61 min, 89.2% (Method A) RT =5.29 min, 99.5% (Method B) 33

(R)-5-amino-2,6-dioxo-N-(6-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide399/3.34 min (Method G) RT = 8.06 min, 99% (Method A) RT = 7.57 min,100% (Method B) 34

(S)-5-amino-2,6-dioxo-N-(6-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide399/1.90 min (Method B) RT = 8.06 min, 98.5% (Method A) RT = 7.57 min,100% (Method B) 35

(S)-5-amino-2,6-dioxo-N-(5-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide399/1.88 min (Method B) RT = 8.11 min, 95.7% (Method A) RT = 7.59 min,98.8% (Method B) 36

(R)-5-amino-2,6-dioxo-N-(5-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide399/1.90 min (Method B) RT = 8.08 min, 95.7% (Method A) RT = 7.58 min,98.8% (Method B) 37

  Isomer A 5-amino-N-((1R)-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-carboxamide 445.0/3.09 min (Method G) RT = 10.02 min, 100% (Method A) RT= 9.20 min, 99.5% (Method B) 38

  Isomer B 5-amino-N-((1R)-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-carboxamide 467.2 (M + Na)/ 2.15 min (Method B) RT = 10.21 min, 91.7%(Method A) RT = 9.29 min, 93.8% (Method B) 39

5-amino-N-(7-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 331/1.67 min (Method B) RT =9.81 min, 97.2% (Method A) RT = 8.92 min, 95.2% (Method B) 40

(R)-5-amino-N-(7-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 319/1.71 min (Method B) RT =6.85 min, 96% (Method A) RT = 6.41 min, 99% (Method B) 41

(S)-5-amino-N-(7-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 319/1.71 min (Method B) RT =6.85 min, 99% (Method A) RT = 6.41 min, 99% (Method B) 42

5-amino-2,6-dioxo-N-((1R,3S)-3- phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 363.3/1.99 min (Method B) RT= 8.06 min, 99.2% (Method A) RT = 7.65 min, 99.1% (Method B) 43

cis-methyl 4-(5-amino-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido) cyclohexanecarboxylate 311.2/1.04 min (Method B) RT = 4.64min, 100% (Method A) RT = 4.32 min, 100% (Method B) 44

5-amino-N-(4-tert-butylcyclohexyl)- 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 309.3/1.49 min (Method D) RT = 8.22min, 91.5% (Method A) RT = 7.33 min, 97.5% (Method B) 45

5-amino-2,6-dioxo-N-(4-oxo- 1,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-8-yl)- 1,2,3,6-tetrahydro-4-pyrimidinecarboxamide 375.0/1.50 min (Method D) 94.9 46

5-amino-2,6-dioxo-N-(4,5,6,7- tetrahydrobenzo[b]thiophen-7-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 307.2/2.98 min (Method J)97.6 47

5-amino-N-(5-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo1,2,3,6-tetrahydropyrimidine-4- carboxamide 331/1.74 min (Method B) RT =6.85 min, 96% (Method A) RT = 6.41 min, 99% (Method B) 48

5-amino-N-(cis-4-(3-(3,4- dichlorophenyl)-1,2,4-oxadiazol-5-yl)cyclohexyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide465.2/2.13 min (Method B) RT = 9.11 min, 86% (Method A) RT = 8.11 min,83.9% (Method B) 49

(R)-5-amino-2,6-dioxo-N-(5- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369/1.95 min (Method B) RT = 8.00 min, 99% (Method A) RT = 7.40 min, 97%(Method B) 50

(S)-5-amino-2,6-dioxo-N-(5- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369/1.95 min (Method B) RT = 8.01 min, 99% (Method A) RT = 7.42 min, 96%(Method B) 51

(R)-5-amino-2,6-dioxo-N-(6- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369.1/2.48 min (Method G) RT = 8.11 min, 99.1% (Method A) RT = 7.52 min,99.6% (Method B) 52

(S)-5-amino-2,6-dioxo-N-(6- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369.2/2.48 min (Method G) RT = 8.11 min, 99.1% (Method A) RT = 7.52 min,99.7% (Method B) 53

(R)-5-amino-2,6-dioxo-N-(7- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369/1.90 min (Method B) RT = 7.74 min, 97% (Method A) RT = 7.16 min, 97%(Method B) 54

(S)-5-amino-2,6-dioxo-N-(7- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide369/1.88 min (Method B) RT = 7.72 min, 97% (Method A) RT = 7.14 min, 99%(Method B) 55

(S)-5-amino-N-(6-bromo-2,3-dihydro- 1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 364.9/1.93 (Method K) 97.1 56

methyl 2-(5-amino-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamido)cyclohexanecarboxylate 311.1/1.51 (Method K) 95.5 57

5-amino-N-(1-isopropyl-4- methylbicyclo[3.1.0]hexan-3-yl)2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 307.1./2.15 (Method K)97.2 58

methyl 3-(5-amino-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamido)cyclohexanecarboxylate 311.1/1.46 (Method K) 98.7 59

5-amino-N-(bi(cyclohexan)-2-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 335.1/2.45 (Method K)100 60

(S)-5-amino-N-(4-bromo-2,3-dihydro- 1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 364.9/1.96 (Method K) 100 61

(1S,2R)-ethyl 2-(5-amino-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido) cyclopentanecarboxylate 311.1/1.54 (Method K) 96.2 62

tert-butyl 3-(5-amino-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido)pyrrolidine-1- carboxylate 240.2/1.66 (Method K) 93.2 63

5-amino-N-((1R,2R)-2- (benzyloxy)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 345.1/1.86 (Method K) 95.464

5-amino-N-((1R,2R)-2-(4- chlorophenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine- carboxamide 349.0/2.11 (Method K) 92.2 65

(R)-5-amino-N-(5-bromo-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 364.9/1.93 (Method K) 92.666

5-amino-N-(8-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 331/1.15 (Method B) RT =5.98 min, 90% (Method A) RT = 5.76 min, 94% (Method B) 67

5-amino-N-((1S,3R)-3-(3,4- dichlorophenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 383.0/2.07 (Method B)RT = 8.95 min, 99.5% (Method A) RT = 8.25 min, 100% (Method B) 68

5-amino-N-((1R,3R)-3-(3,4- dichlorophenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 383.0/2.03 (Method B)RT = 9.00 min, 99.1% (Method A) RT = 8.28 min, 99.2% (Method B) 69

5-amino-N-((1S,3S)-3-(3,4- dichlorophenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 383.1/2.03 (Method B)RT = 8.96 min, 94.0% (Method A) RT = 8.26 min, 100% (Method B) 70

(R)-5-amino-N-(5-methoxy-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 317/1.55 (Method B) RT =5.87 min, 94% (Method A) RT = 5.50 min, 99% (Method B) 71

5-amino-2,6-dioxo-N-((1S,4R)-4- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 399.2/2.05 (Method B)RT = 8.34 min, 92.4% (Method A) RT = 7.84 min, 92.4% (Method B) 72

  Isomer A 5-amino-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide317.1/1.65 (Method B) RT = 6.05 min, 95.6% (Method A) RT = 5.71 min,99.2% (Method B) 73

  Isomer B 5-amino-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide317.1/1.65 (Method B) RT = 6.04 min, 96.5% (Method A) RT = 5.71 min,98.9% (Method B) 74

5-amino-N-((1R,3S)-3-(3,4- dichlorophenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 383.1/2.03 (Method B)RT = 8.39 min, 99.4% (Method A) RT = 7.74 min, 99.6% (Method B) 75

5-amino-2,6-dioxo-N-((1R,3S)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 315.1/1.81 (Method H) RT = 6.47 min,99.5% (Method A) RT = 6.05 min, 100% (Method B) 76

5-amino-2,6-dioxo-N-((1S,3S)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 315.1/1.79 (Method H) RT = 6.44 min,100% (Method A) RT = 6.03 min, 100% (Method B) 77

5-amino-2,6-dioxo-N-((1R,3R)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 315.1/3.18 (Method A) RT = 10.41 min,96.1% (Method A) RT = 11.01 min, 98.0% (Method B) 78

5-amino-2,6-dioxo-N-((1S,3R)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 315.1/1.85 (Method H) RT = 10.43 min,99.3% (Method A) RT = 11.03 min, 99.4% (Method B) 79

5-amino-N-((1S,3R)-3-(6- methoxypyridin-3-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 346.2/1.23 (MethodB) RT = 4.57 min, 99.3% (Method A) RT = 5.23 min, 99.2% (Method B) 80

5-amino-N-((1R,3R)-3-(6- methoxypyridin-3-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 346.2/1.24 (MethodB) RT = 4.62 min, 99.4% (Method A) RT = 5.27 min, 99.8% (Method B) 81

5-amino-N-(1-(3-methoxyphenyl)-5- oxopyrrolidin-3-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 360.1/1.33 (Method A) RT = 4.89 min,94% (Method A) RT = 4.76 min, 96% (Method B) 82

(R)-5-amino-N-(5-(benzyloxy)- 1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/2.34 (MethodB) RT = 8.82 min, 96% (Method A) RT = 8.18 min, 99% (Method B) 83

(R)-5-amino-N-(6-(benzyloxy)- 1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/2.01 (MethodB) RT = 9.01 min, 94% (Method A) RT = 8.39 min, 93% (Method B) 84

(R)-5-amino-2,6-dioxo-N-(5- phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide393.1/2.04 (Method B) RT = 8.8 min, 94% (Method A) RT = 8.2 min, 97%(Method B) 85

(R)-5-amino-2,6-dioxo-N-(6- phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide393.1/3.75 (Method A) RT = 8.73 min, 92% (Method A) RT = 8.16 min, 96%(Method B) 86

(R)-5-ammo-N-(4-(benzyloxy)-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 393.1/1.97 (Method B) RT =8.35 min, 95.4% (Method A) RT = 7.88 min, 95.2% (Method B) 87

(R)-5-amino-N-(5-(benzyloxy)-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 393.1/1.96 (Method B) RT =8.29 min, 95% (Method A) RT = 7.81 min, 99% (Method B) 88

(R)-5-amino-2,6-dioxo-N-(4- phenoxy-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 379.1/1.99 (Method B) RT =8.30 min, 95.9% (Method A) RT = 7.79 min, 99.3% (Method B) 89

(R)-5-amino-2,6-dioxo-N-(5- phenoxy-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 379.1/1.99 (Method B) RT =8.27 min, 96.4% (Method A) RT = 7.75 min, 98.8% (Method B) 90

(S)-5-amino-N-(6-(benzyloxy)-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 393.1/1.93 (Method B) RT =8.10 min, 98% (Method A) RT = 7.74 min, 100% (Method B) 91

(R)-5-amino-N-(6-(benzyloxy)-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 393.1/1.82 (Method B) RT =8.21 min, 98% (Method A) RT = 7.73 min, 95% (Method B) 92

(S)-5-amino-N-(5-(benzyloxy)- 1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/2.02 (MethodB) RT = 8.89 min, 94% (Method A) RT = 8.33 min, 83% (Method B) 93

(S)-5-amino-N-(6-(benzyloxy)- 1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/2.02 (MethodB) RT = 8.68 min, 91% (Method A) RT = 8.15 min, 83% (Method B) 94

5-amino-N-((1R,2R)-2- (benzyloxy)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 245.1/1.67 (Method B) RT =6.65 min, 92.8% (Method A) RT = 6.08 min, 97% (Method B) 95

5-amino-N-(cis-4-(benzyloxy) cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 359.2/1.82 (Method B) RT = 7.98 min,94.7% (Method A) RT = 7.77 min, 95.3% (Method B) 96

(R)-5-amino-N-(5-(2- fluorobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 424/2.12 (Method B) RT = 8.74 min, 91.3% (Method B) 97

(S)-5-amino-N-(5-(2- fluorobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 424/2.19 (Method B) RT = 9.43 min, 89.9% (Method A) RT =8.73 min, 100% (Method B) 98

  Diastereomer mixture 5-amino-2,6-dioxo-N-(3-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 329.2/1.97(Method B) RT = 9.31 min, 98.6% (Method A) RT = 9.10 min, 99.7% (MethodB) 99

  Isomer A 5-amino-2,6-dioxo-N-(3- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 329.2/1.95 (Method B) RT = 8.72 min,99.4% (Method A) RT = 8.54 min, 99.4% (Method B) 100

  Isomer B 5-amino-2,6-dioxo-N-(3- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 329.1/1.91 (Method B) RT = 8.65 min,96.9% (Method A) RT = 8.46 min, 100% (Method B) 101

  Isomer C 5-amino-2,6-dioxo-N-(3- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 329.1/1.91 (Method B) RT = 8.70 min,100% (Method A) RT = 8.54 min, 100% (Method B) 102

5-amino-N-(3-(1-benzyl-1H-pyrazol- 4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 395.0/0.72 (Method M) RT = 6.61 min,97% (Method A) RT = 6.49 min, 95% (Method B) 103

(R)-5-amino-N-(5-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 331.1/1.70 (Method B) RT =6.08 min, 95.3% (Method A) RT = 5.71 min, 100% (Method B) 104

5-amino-N-(3-(3-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.0/0.91 (Method M) RT =9.27 min, 100% (Method A) RT = 8.75 min, 99% (Method B) 105

(R)-5-amino-N-(6-benzamido-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 420.1/1.69 (Method B) RT = 6.72 min, 94% (Method A) RT =6.34 min, 94% (Method B) 106

5-amino-N-(3-(4-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.1/2.18 (Method B) RT =6.28 min, 100% (Method B) 107

5-amino-N-(3-(4-methoxyphenyl) cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 345.0/1.75 (Method B) RT = 8.0 min,97.7% (Method A) RT = 7.9 min, 98.4% (Method B) 108

5-amino-N-(5,6-dimethoxy-1,2,3,4- tetrahydronaphthalen-2-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 361.0/1.58 (Method B) RT =7.07 min, 90.8% (Method A) RT = 7.09 min, 100% (Method B) 109

5-amino-N-(5,8-dimethoxy-6-methyl- 1,2,3,4-tetrahydronaphthalen-2-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 375.2/1.99 (MethodB) RT = 8.14 min, 99.2% (Method A) RT = 7.99 min, 100% (Method B) 110

(R)-5-amino-N-(8-methoxy-1,2,3,4- tetrahydronaphthalen-2-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 331.0/1.72 (Method B) RT =7.86 min, 98.6% (Method A) RT = 7.83 min, 99.1% (Method B) 111

(R)-5-amino-2,6-dioxo-N-(5- phenethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide405.1/2.15 (Method B) RT = 9.48 min, 98% (Method A) RT = 8.66 min, 99%(Method B) 112

(R)-5-amino-2,6-dioxo-N-(5-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 377.1/2.02 (Method B) RT =8.52 min, 97% (Method A) RT = 7.96 min, 99% (Method B) 113

(R)-5-amino-N-(5- (cyclopentylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 399.1/2.32 (Method B) RT = 10.4 min, 91.2% (Method A) RT =9.11 min, 99% (Method 114

5-amino-N-(cis-4-(4-(benzyloxy) phenyl)cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 435.1/2.19 (Method B) RT = 10.8 min,99.2% (Method A) RT = 10.2 min, 98.3% (Method B) 115

5-amino-N-(cis-4- benzamidocyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 372.1/0.61 (Method M) RT =5.12 min, 93% (Method A) RT = 4.87 min, 91% (Method B) 116

5-amino-2,6-dioxo-N-(cis-4-(2- phenylacetamido)cyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 386.0/0.62 (Method M) RT = 5.27 min,100% (Method A) RT = 5.06 min, 97% (Method B) 117

N-(cis-4-(5-amino-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamido)cyclohexyl)benzo[d] thiazole-2-carboxamide 428.9/0.73(Method M) RT = 6.74 min, 95% (Method A) RT = 6.51 min, 99% (Method B)118

5-amino-2,6-dioxo-N-(cis-4-(3- phenylureido)cyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 387.0/0.64 (Method M) RT = 5.72 min,100% (Method A) RT = 5.47 min, 99% (Method B) 119

benzyl cis-4-(5-amino-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido)cyclohexylcarbamate 402.1/0.73 (Method M) RT = 6.70 min,100% (Method A) RT = 6.49 min, 99% (Method B) 120

5-amino-N-(cis-4-(4-(2- methoxyethoxy)benzamido)cyclohexyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide445.9/0.62 (Method M) RT = 5.19 min, 97% (Method A) RT = 4.98 min, 95%(Method B) 121

5-amino-N-(cis-4-(3- ethoxybenzamido)cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 416.0/0.68 (Method M)RT = 6.10 min, 99% (Method A) RT = 5.86 min, 97% (Method B) 122

5-amino-N-(cis-4-(3-(benzyloxy) benzamido)cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 477.9/0.79 (Method M) RT =7.63 min, 94% (Method A) RT = 7.42 min, 94% (Method B) 123

(R)-5-amino-N-(5-(benzylamino)- 1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 405/1.68 (MethodB) RT = 6.81 min, 92.8% (Method A) RT = 6.41 min, 89.4% (Method B) 124

(R)-5-amino-N-(5-benzamido-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 420.1/1.58 (Method B) RT = 6.24 min, 90% (Method A) RT =5.91 min, 94% (Method B) 125

(R)-5-amino-2,6-dioxo-N-(5- (phenylsulfonamido)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide456.1/1.59 (Method B) RT = 6.52 min, 93% (Method A) RT = 6.24 min, 89%(Method B) 126

(R)-5-amino-2,6-dioxo-N-(5- (phenylamino)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide392.1/1.89 (Method B) RT = 8.15 min, 89% (Method A) RT = 7.69 min, 92%(Method B) 127

5-amino-N-(3-(1-benzyl-1H-pyrazol- 4-yl)cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 409.2/1.89 (Method B) RT = 7.69 min,96.8% (Method A) RT = 7.87 min, 96.2% (Method B) 128

5-amino-N-(3-(4-(4- methylphenylsulfonamido)phenyl)cyclohexyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide498.1/1.86 (Method B) RT = 9.43 min, 95.0% (Method A) RT = 9.49 min,97.3% (Method B) 129

5-amino-2,6-dioxo-N-((1S,3S)-3- (phenylcarbamoyl)cyclopentyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 358.1/1.42 (Method B) RT =6.47 min, 95% (Method A) RT = 6.54 min, 93% (Method B) 130

5-amino-2,6-dioxo-N-((1R,3S)-3- (phenylcarbamoyl)cyclopentyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 358.0/1.47 (Method B) RT =6.80 min, 85.3% (Method A) RT = 6.91 min, 91.6% (Method B) 131

  Isomer A 5-amino-N-(3-(1-benzyl-1H-pyrazol-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide394.9/0.72 (Method M) RT = 6.61 min, 97% (Method A) RT = 6.49 min, 95%(Method B) 132

  Isomer B 5-amino-N-(3-(1-benzyl-1H-pyrazol-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide395.0/0.71 (Method M) RT = 6.48 min, 100% (Method A) RT = 6.35 min, 99%(Method B) 133

  Isomer C 5-amino-N-(3-(1-benzyl-1H-pyrazol-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide395.0/0.71 (Method M) RT = 6.55 min, 100% (Method A) RT = 6.41 min, 96%(Method B) 134

  Isomer D 5-amino-N-(3-(1-benzyl-1H-pyrazol-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide395.0/0.72 (Method M) RT = 6.56 min, 100% (Method A) RT = 6.43 min, 100%(Method B) 135

5-amino-2,6-dioxo-N-(3-(2-(6- phenylbenzo[d]thiazol-2-yl)acetamido)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide505.1/1.88 (Method B) RT = 8.29 min, 95% (Method A) RT = 8.41 min, 93%(Method B) 136

5-amino-N-((1S,3R)-3-((R)-5- (benzyloxy)-1,2,3,4-tetrahydronaphthalen-1- ylcarbamoyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 540.3 [M + Na]/ 2.09 (MethodB) RT = 6.68 min, 99.1% (Method A) RT = 6.11 min, 99.3% (Method B) 137

(R)-5-amino-2,6-dioxo-N-(4-phenyl- 2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 363.1/1.93 (Method B) RT = 9.09 min,89.8% (Method A) RT = 8.69 min, 91% (Method B) 138

(R)-5-amino-2,6-dioxo-N-(6-phenyl- 2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 363.1/1.95 (Method B) RT = 9.12 min,91% (Method A) RT = 8.72 min, 94% (Method B) 139

(S)-5-amino-2,6-dioxo-N-(6-phenyl- 2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 363.1/1.95 (Method B) RT = 9.13 min,91% (Method A) RT = 8.72 min, 94% (Method B) 140

5-amino-N-(3-(4-(4-bromophenyl)- 1H-pyrazol-1-yl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 461.0/1.96 (Method B)RT = 9.34 min, 95% (Method A) 141

5-amino-N-(3-(2-methoxyphenyl) cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 345.1/1.84 (Method B) RT = 7.49 min,96% (Method A) RT = 7.28 min, 96% (Method B) 142

5-amino-N-(3-(4- isopropoxyphenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 373.2/1.98 (Method B)RT = 8.66 min, 99% (Method B) 143

5-amino-N-(3-(4-(neopentyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 401.2/2.27 (Method B) RT =11.43 min, 93% (Method A) RT = 10.22 min, 92% (Method B) 144

5-amino-2,6-dioxo-N-(3-(6- phenylbenzo[d]thiazol-2-yl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 448.2/2.23(Method B) RT = 9.70 min, 97% (Method A) RT = 9.29 min, 100% (Method B)145

5-amino-N-(3-(4-isobutoxyphenyl) cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 387.2/2.17 (Method B) RT = 11.00 min,100% (Method A) RT = 10.26 min, 100% (Method B) 146

5-amino-2,6-dioxo-N-((1R,3R)-3- ((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide412.1/1.67 (Method B) RT = 6.94 min, 90% (Method A) RT = 6.89 min, 91%(Method B) 147

5-amino-2,6-dioxo-N-((1R,3R)-3-(cis- 4-phenylcyclohexylcarbamoyl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 440.1/1.85(Method B) RT = 7.9 min, 90% (Method A) RT = 7.7 min, 90% (Method B) 148

5-amino-N-((1R,3R)-3- (benzo[d]thiazol-2-ylmethylcarbamoyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 429.1/1.56 (Method B)RT = 5.91 min, 94% (Method A) RT = 5.88 min, 94% (Method B) 149

5-amino-N-((1R,3R)-3-(1-benzyl-1H- pyrazol-4-ylcarbamoyl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 438.1/1.62 (MethodB) RT = 9.92 min, 90% (Method A) RT = 9.46 min, 94% (Method B) 150

5-amino-2,6-dioxo-N-((1R,3R)-3-(cis- 4-(3-(trifluoromethyl)phenyl)cyclohexylcarbamoyl) cyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 508.3/2.07 (Method B) RT = 8.58 min,88.5% (Method B) 151

  Isomer A 5-amino-N-(3-(4-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.1/2.12 (Method B) RT =10.95 min, 99.3% (Method A) RT = 10.50 min, 99.5% (Method B) 152

  Isomer B 5-amino-N-(3-(4-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 421.1/2.12 (Method B) RT =9.79 min, 98.4% (Method A) RT = 9.44 min, 100% (Method B) 153

  Isomer C 5-amino-N-(3-(4-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.1/2.14 (Method B) RT =9.87 min, 98.8% (Method A) RT- 9.47 min, 98.7% (Method B) 154

  Isomer D 5-amino-N-(3-(4-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.1/2.13 (Method B) RT =9.78 min, 97.9% (Method A) RT = 9.43 min, 97.5% (Method B) 155

  Isomer A 5-amino-N-(3-(3-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 421.0/0.91 (Method M) RT =9.23 min, 98% (Method A) RT = 8.78 min, 98% (Method B) 156

  Isomer B 5-amino-N-(3-(3-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.0/0.91 (Method M) RT =9.21 min, 96% (Method A) RT = 8.75 min, 95% (Method B) 157

  Isomer C 5-amino-N-(3-(3-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 421.0/0.91 (Method M) RT =9.20 min, 97% (Method A) RT = 8.73 min, 91% (Method B) 158

  Isomer D 5-amino-N-(3-(3-(benzyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 421.0/0.91 (Method M) RT =9.21 min, 91% (Method A) RT = 8.74 min, 93% (Method B) 159

5-amino-2,6-dioxo-N-((1S,3R)-3-(4- (1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide423.0/1.03 (Method K) 99.3 160

ethyl 2-(4-(4-((1R,3S)-3-(5-amino 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamido)cyclopentyl)phenyl)1H-pyrazol-1-yl)acetate 467.0/1.26 (Method K) 99.6 161

5-amino-N-((1S,3R)-3-(3′,4′- dimethoxybiphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide451.0/1.50 (Method K) 100 162

N-((1S,3R)-3-(2′-acetamidobiphenyl- 4-yl)cyclopentyl)-5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 448.0/1.24 (Method K) 100163

5-amino-N-((1S,3R)-3-(4-(1-methyl- 1H-pyrazol-5-yl)phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide395.0/1.14 (Method K) 100 164

5-amino-N-((1R,3S)-3-(4-(1-(2- morpholinoethyl)-1H-pyrazol-4-yl)phenyl)cyclopentyl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 494.0/0.86 (Method K) 100 165

5-amino-N-((1R,3S)-3-(4-(5-methyl- 1-phenyl-1H-pyrazol-4-yl)phenyl)cyclopentyl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 471.0/1.61 (Method K) 100 166

5-amino-N-((1S,3R)-3-(3′- (dimethylamino)biphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide434.0/1.80 (Method K) 100 167

5-amino-N-((1S,3R)-3-(biphenyl-4- yl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 391.0/1.70 (Method K) 100 168

5-amino-N-((1S,3R)-3-(4′- methoxybiphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 421.0/1.65 (MethodK) 100 169

5-amino-N-((1S,3R)-3-(4′- methylbiphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 405.0/1.87 (MethodK) 100 170

5-amino-N-((1S,3R)-3-(4′- chlorobiphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 424.9/1.92 (Method K)100 171

5-amino-N-((1S,3R)-3-(4-(4-methyl- 2-phenylthiazol-5-yl)phenyl)cyclopentyl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 488.0/1.91 (Method K) 99.4 172

5-amino-N-((1S,3R)-3-(4-(1-isobutyl- 1H-pyrazol-4-yl)phenyl)cyclopentyl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 437.0/1.51 (Method K) 100 173

5-amino-N-((1R,3S)-3-(4-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)cyclopentyl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 463.0/1.62 (Method K) 99.3 174

5-amino-N-((1S,3R)-3-(2′- (hydroxymethyl)biphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide421.0/1.35 (Method K) 100 175

5-amino-2,6-dioxo-N-((1R,3S)-3-(4- (quinolin-5-yl)phenyl)cyclopentyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 442.0/1.44 (Method K) 100176

5-amino-2,6-dioxo-N-((1S,3R)-3-(4- (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)cyclopentyl)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 465.2/1.96 (Method K) 100 177

5-amino-N-((1S,3R)-3-(4′- (hydroxymethyl)biphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide421.0/1.25 (Method K) 100 178

5-amino-N-((1S,3R)-3-(3′- (hydroxymethyl)biphenyl-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide421.0/1.30 (Method K) 100 179

5-amino-N-((1S,3R)-3-(4-(1-benzyl- 1H-pyrazol-4-yl)phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide471.0/1.52 (Method K) 100 180

5-amino-N-((1S,3R)-3-(2′-carbamoyl-[1,1′-biphenyl]-4-yl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 434.1/1.58 (Method K)100 182

5-amino-2,6-dioxo-N-(1- phenylpyrrolidin-3-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.2/1.56 (Method B) RT = 7.10 min,98.9% (Method A) RT = 7.69 min, 97.1% (Method B) 183

5-amino-N-(1-(3-chloropyridin-2- yl)piperidin-3-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 365.1/1.41 (Method K) 94.7 184

5-amino-2,6-dioxo-N-(1-(4- (trifluoromethyl)pyrimidin-2-yl)piperidin-3-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 399.9/1.33(Method K) 100 185

5-amino-N-(1-(4-chloro-6- methylpyrimidin-2-yl)piperidin-3-yl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 380/0.92 (MethodK) 99.2 186

5-amino-N-(1-(3-chloropyridin-2- yl)pyrrolidin-3-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 350.9/1.06 (Method K) 92.3 187

5-amino-N-(1-(1-benzyl-3-bromo-1H1,2,4-triazol-5-yl)pyrrolidin-3-yl)-2,6dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 474.8/1.13 (Method K)96.4 188

5-amino-N-(1-(5-carbamoylpyridin-2-yl)pyrrolidin-3-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 359.9/0.53 (Method K) 100 189

N-(1-(1H-pyrazolo[3,4-d]pyrimidin- 4-yl)pyrrolidin-3-yl)-5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 358.0/0.51 (Method K)97.9 190

5-amino-2,6-dioxo-N-(1-(5- (trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 385.0/1.67(Method K) 100 191

(R)-5-amino-2,6-dioxo-N-(1- phenylpyrrolidin-3-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.3/1.50 (Method H) RT = 5.93 min,99.4% (Method A) RT = 5.66 min, 98.7% (Method B) 192

(S)-5-amino-2,6-dioxo-N-(1- phenylpyrrolidin-3-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.2/1.77 (Method H) RT = 5.93 min,99.3% (Method A) RT = 5.66 min, 98.5% (Method B) 194

  Enantiomer A 5-amino-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer A) 331/1.66 min (Method B) RT = 6.53 min, 96.3%(Method A) RT = 6.11 min, 99.6% (Method B) 195

  Enantiomer B 5-amino-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer B) 331/1.66 min (Method B) RT = 6.53 min, 94.3%(Method A) RT = 6.11 min, 99.2% (Method B) 196

  Enantiomer B 5-amino-N-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide (Enantiomer B)380/1.67 min (Method G) RT = 5.49 min, 97% (Method A) RT = 5.35 min, 98%(Method B) 197

  Enantiomer B 5-amino-N-(chroman-4-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide (Enantiomer B) 303/1.47 min(Method B) RT = 5.62 min, 99% (Method A) RT = 5.34 min, 100% (Method B)198

  Enantiomer A 5-amino-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer A) 331.0 (M + H)/ 1.74 min (Method B) RT = = 6.6min, 95% (Method A) RT = 6.1 min, 98% (Method B) 199

  Enantiomer B 5-amino-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer B) 331.0 (M + H)/ 1.73 min (Method B) RT = 6.6min, 91% (Method A) RT = 6.1 min, 97% (Method B) 200

  Enantiomer B 5-amino-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer B) 331/1.66 min (Method B) RT = 6.41 min, 95%(Method A) RT = 6.13 min, 97% (Method B) 201

  Enantiomer A 5-amino-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo 1,2,3,6-tetrahydropyrimidine-4-carboxamide (Enantiomer A) 331/0.94min (Method G) RT = 6.32 min, 96%(Method A) RT = 5.97 min, 94% (Method B) 204

5-amino-3-(3,4-dichlorophenyl)-2,6 dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 472.9/2.20 min (Method B) RT= 9.71 min, 100% (Method A) RT = 8.76 min, 100% (Method B) 206

5-(isobutylamino)-2,6-dioxo-N-(cis-4- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 385.2/2.19 min (Method B) RT = 8.92min, 96.9% (Method A) RT = 8.82 min, 96.9% (Method B) 207

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(3- phenylpropylamino)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 447.1/2.79 min (Method K) 94.2 208

5-(cyclopentylamino)-2,6-dioxo-N- (cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 397.1/2.55 min (Method K) 94.8 209

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(pyridin-3-ylmethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 420.1/1.9 min(Method K) 92.3 210

5-(isopentylamino)-2,6-dioxo-N-(cis- 4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 399.1/2.7 min (Method K) 93.2 211

5-(2-morpholinoethylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 442.1/2.05 min (Method K)92.6 212

5-(2-(hydroxymethyl)benzylamino)- 2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 449.0/2.2min (Method K) 91.9 213

5-(2-(1H-imidazol-4-yl)ethylamino)- 2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 423.1/1.7min (Method K) 99.1 214

5-(2-methoxyethylamino)-2,6-dioxo- N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 387.1/2.1 min (Method K) 95.8 215

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(2-(trifluoromethyl)benzylamino)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 487.0/2.71 min (Method K) 92.6 216

5-(3-(1H-imidazol-1-yl) propylamino)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 437.2/1.88min (Method K) 97.6 217

5-(2-hydroxyethylamino)-2,6-dioxo- N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 373.1/1.83 min (Method K) 100 218

5-(4-chlorophenethylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 467.1/2.91 min (Method K)100 219

5-(3-morpholinopropylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 456.2/1.96 min (Method K)99.0 220

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(4-(trifluoromethyl)benzylamino)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 487.1/2.82 min (Method K) 96.3 221

5-(2-chlorophenethylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 467.1/2.84 min (Method K)100 222

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(3-(trifluoromethyl)benzylamino)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 487.1/2.8 min (Method K) 95.5 223

5-(1-benzylpyrrolidin-3-ylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 488.2/2.47 min (Method K)98.7 224

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(1,2,3,4-tetrahydronaphthalen-1-ylamino)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 459.1/2.86 min (Method K) 97.8 225

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(pyridin-2-ylmethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 420.1/2.15min (Method K) 92.6 226

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(4-sulfamoylphenethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide512.1/2.1 min (Method K) 99.2 227

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(pyridin-4-ylmethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 420.1/1.91min (Method K) 99.0 228

2,6-dioxo-N-(cis-4- phenylcyclohexyl)-5-(2,2,2-trifluoroethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide411.1/3.86 min (Method A) RT = 8.84 min, 97.5% (Method A) RT = 8.02 min,98.2% (Method B) 229

5-(ethylamino)-2,6-dioxo-N-(cis-4- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 357.2/2.25 min (Method K) 91.1 230

5-(1-methylpiperidin-4-ylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 426.2/1.6 min (Method K)98.3 231

5-((1R,2R,4S)-bicyclo[2.2.1]heptan- 2-ylamino)-2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 423.2/2.82min (Method K) 100 232

5-((S)-1-cyclohexylethylamino)-2,6- dioxo-N-(cis-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 439.2/3.11 min (Method K)100 233

5-(cyclobutylamino)-2,6-dioxo-N- (cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 383.2/2.48 min (Method K) 97.3 234

5-(2-hydroxy-2-methylpropylamino)- 2,6-dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 401.3/1.55min (Method K) 98.7 235

5-(1-hydroxypropan-2-ylamino)-2,6- dioxo-N-(cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 387.4/1.4 min (Method K)87.3 236

5-(3-fluoro-5-(trifluoromethyl) benzylamino)-2,6-dioxo-N-((1s,4s)-4-phenylcyclohexyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 505.0/2.16min (Method K) 100 237

2,6-dioxo-N-((1s,4s)-4- phenylcyclohexyl)-5-(2-(piperidin-1-yl)ethylamino)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 440.2/1.75min (Method K) 100 242

5-hydroxy-1-methyl-2,6-dioxo-N- (cis-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 358.1/2.12 min (Method B) RT = 8.46min, 100% (Method A) RT = 7.56 min, 100% (Method B) 243

5-hydroxy-2,6-dioxo-N-(cis-4- phenylcyclohexyl)-1-(2,2,2-trifluoroethyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 412/2.11 min(Method B) RT = 9.22 min, 100% (Method A) RT = 8.20 min, 100% (Method B)244

1-benzyl-5-hydroxy-2,6-dioxo-N-(4- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 420.1/2.25 min (Method B) RT = 10.09min, 100% (Method A) RT = 9.02 min, 100% (Method B) 245

(S)-5-hydroxy-2,6-dioxo-N-(1,2,3,4- tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 301/1.75 min (Method B) RT = 6.03min, 98.2% (Method A) RT = 5.64 min, 97.8% (Method B) 246

(S)-5-hydroxy-2,6-dioxo-N-(5-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide400.1/1.45 min (Method D) RT = 7.76 min, 100% (Method A) RT = 7.29 min,100% (Method B) 247

5-hydroxy-2,6-dioxo-N-((1S,3S)-3- phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 364.1/2.02 min (Method B) RT= 7.97 min, 100% (Method A) RT = 7.51 min, 100% (Method B) 248

(R)-5-hydroxy-2,6-dioxo-N-(6- (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 356.1/1.86 min(Method B) RT = 7.10 min, 93% (Method A) RT = 6.64 min, 90.5% (Method B)249

(R)-5-hydroxy-2,6-dioxo-N-(5- (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 378.2 (M + Na)/3.39 min (Method J) RT = 7.16 min, 100% (Method A) RT = 6.64 min, 89.7%(Method B) 250

5-hydroxy-2,6-dioxo-N-((1R,4R)-4- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 400.2/2.03 min (MethodH) RT = 7.80 min, 100% (Method A) RT = 7.25 min, 100% (Method B) 251

N-((1R,3R)-3-(3,4- dichlorophenyl)cyclopentyl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 384.2/2.05min (Method H) RT = 8.32 min, 98.9% (Method A) RT = 7.72 min, 98.9%(Method B) 252

5-hydroxy-2,6-dioxo-N-((1s,4s)-4- phenylcyclohexyl)-1-(3,3,3-trifluoropropyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 426.2/2.16min (Method B) RT = 9.86 min, 100% (Method A) RT = 8.86 min, 100%(Method B) 253

5-hydroxy-1-isobutyl-2,6-dioxo-N- ((1s,4s)-4-phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 386.3/2.25 min (Method B) RT = 10.12min, 98.9% (Method A) RT = 8.86 min, 98.8% (Method B) 254

(R)-5-hydroxy-2,6-dioxo-N-(5- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide370.1/1.94 min (Method B) RT = 7.67 min, 97% (Method A) RT = 7.19 min,98% (Method B) 255

(R)-5-hydroxy-2,6-dioxo-N-(5-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide400.2/1.95 min (Method B) RT = 7.85 min, 99% (Method A) RT = 7.38 min,99% (Method B) 256

(R)-5-hydroxy-2,6-dioxo-N-(6-(2,2,2- trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide400.2/1.89 min (Method B) RT = 7.76 min, 99% (Method A) RT = 7.32 min,99% (Method B) 257

5-hydroxy-2,6-dioxo-N-((1s,4s)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 398.1/2.01 min (Method B) RT = 8.36 min, 92.2% (Method A) RT= 7.79 min, 92.2% (Method B) 258

(R)-N-(5-(benzyloxy)-1,2,3,4- tetrahydronaphthalen-1-yl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/2.02min (Method B) RT = 8.50 min, 93.8% (Method A) RT = 7.84 min, 96.7%(Method B) 259

(S)-N-(6-(benzyloxy)-2,3-dihydro- 1H-inden-1-yl)-5-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 394.1/1.98 min (Method B) RT= 8.08 min, 94.5% (Method A) RT = 7.51 min, 99.3% (Method B) 260

N-((1s,4s)-4-benzamidocyclohexyl)- 5-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 373.1/0.61 min (Method M) RT = 5.25min, 100% (Method A) RT = 5.01 min, 95% (Method B) 261

(R)-5-hydroxy-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 332.1/1.76 min (Method B) RT = 6.01 min, 99.3% (Method A) RT= 5.66 min, 100% (Method B) 262

(R)-5-hydroxy-N-(5-hydroxy-2,3- dihydro-1H-inden-1-yl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 304.1/1.32 min (Method B) RT= 6.01 min, 93.1% (Method A) RT = 5.66 min, 100% (Method B) 263

N-((1S,3R)-3-((R)-5-(benzyloxy)- 1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)cyclopentyl)-5-hydroxy- 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 519.3/2.04 min (Method B) RT = 13.99min, 96.1% (Method A) RT = 14.3 min, 96.3% (Method B) 264

(R)-5-hydroxy-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 332.1/1.75 min (Method B) RT = 6.51 min, 91.4% (Method A) RT= 6.13 min, 96.1% (Method B) 265

(S)-5-hydroxy-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamide 332.1/1.70 min (Method B) RT = 6.5 min, 87.2% (Method A) RT= 6.1 min, 98.2% (Method B) 266

(S)-5-hydroxy-2,6-dioxo-N-(5- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide370.1/1.88 min (Method B) NA 272

5-hydroxy-2,6-dioxo-N-((1R,3R)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.2/1.91 min (Method B) RT = 8.83min, 97.0% (Method C) R= 8.35 min, 96.0% (Method D) 273

5-hydroxy-2,6-dioxo-N-((1S,3R)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.1/3.26 min (Method A) RT = 8.83min, 97.0% (Method A) RT = 8.35 min, 96.0% (Method B) 274

(S)-5-hydroxy-2,6-dioxo-N-(1- phenylpyrrolidin-3-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 317.2/1.58 min (Method B) RT = 5.84min, 99.4% (Method A) RT = 5.64 min, 99.4% (Method B) 275

5-hydroxy-2,6-dioxo-N-((1S,3S)-3- phenylcyclopentyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 316.2/1.91 min (Method B) RT = 7.01min, 96.8% (Method A) RT = 6.71 min, 96.2% (Method B) 276

(R)-5-hydroxy-2,6-dioxo-N-(1,2,3,4- tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 302.1/1.83 min (Method B) RT = 7.43min, 98.3% (Method A) RT = 8.03 min, 100% (Method B) 277

5-hydroxy-2,6-dioxo-N-((1S,3S)-3- phenylcyclohcxyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 330.0/1.91 min (Method B) RT = 6.01min, 99.3% (Method A) RT = 5.66 min, 100% (Method B) 278

5-hydroxy-2,6-dioxo-N-((1R,3R)-3- phenylcyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 330.1/1.94 min (Method B) RT = 7.14min, 90.3% (Method A) RT = 6.72 min, 97.3% (Method B) 279

5-hydroxy-2,6-dioxo-N-(cis-4-(2- phenylacetamido)cyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 387.0/0.62 min (Method M) RT = 5.30min, 98% (Method A) RT = 5.07 min, 97% (Method B) 280

5-hydroxy-2,6-dioxo-N-(cis-4-(3- phenylureido)cyclohexyl)-1,2,3,6-tetrahydropyrimidine-4-carboxamide 388.0/0.64 min (Method M) RT = 5.66min, 100% (Method A) RT = 5.41 min, 95% (Method B) 281

benzyl cis-4-(5-hydroxy-2,6-dioxo- 1,2,3,6-tetrahydropyrimidine-4-carboxamido)cyclohexylcarbamate 402.9/0.73 min (Method M) RT = 6.66 min,97% (Method A) RT = 6.45 min, 95% (Method B) 282

N-(3-(3-(benzyloxy)phenyl) cyclopentyl)-5-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 422.0/0.93 min (Method M) RT= 9.18 min, 96% (Method A) RT = 8.70 min, 95% (Method B) 283

N-(3-(1-benzyl-1H-pyrazol-4- yl)cyclopentyl)-5-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 396.0/0.72 min (Method M) RT= 6.54 min, 96% (Method A) RT = 6.43 min, 96% (Method B) 284

5-hydroxy-2,6-dioxo-N-(5-phenethyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 406.1/2.15 min (Method B) RT= 9.51 min, 94% (Method A) RT = 8.72 min, 99.3% (Method B) 285

5-hydroxy-2,6-dioxo-N-(5-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 378.1/2.01 min (Method B) RT= 8.58 min, 88% (Method A) RT = 8.02 min, 95% (Method B) 286

(R)-N-(5-(benzylamino)-1,2,3,4- tetrahydronaphthalen-1-yl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 407.1/1.71min (Method B) RT = 6.79 min, 89% (Method A) RT = 6.38 min, 97% (MethodB) 287

5-hydroxy-2,6-dioxo-N-(5- (phenylsulfonamido)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide456/1.63 min (Method B) RT = 6.23 min, 92.9% (Method A) RT = 5.99 min,91.4% (Method B) 288

(R)-N-(6-benzamido-1,2,3,4- tetrahydronaphthalen-1-yl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 420/1.75min (Method B) RT = 9.11 min, 100% (Method A) RT = 8.91 min, 100%(Method B) 289

N-(3-(1-benzyl-1H-pyrazol-4- yl)cyclohexyl)-5-hydroxy-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 410.1/1.79 min (Method B)Racemic mixture 290

5-hydroxy-2,6-dioxo-N-((1S,3S)-3- (phenylcarbamoyl)cyclopentyl)-1,2,3,6-tetrahydropyrimidine-4- carboxamide 359.1/1.42 min (Method B) RT= 6.51 min, 93% (Method A) RT = 6.62 min, 93% (Method B) 291

(R)-N-(5-(cyclopentylmethoxy)- 1,2,3,4-tetrahydronaphthalen-1-yl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 400.1/2.24min (Method B) RT = 10.99 min, 90% (Method A) RT = 10.78 min, 93%(Method B) 292

5-hydroxy-N-(3-(2- methoxyphenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 346.1/2.09 min (MethodB) RT = 8.34 min, 97% (Method A) RT = 8.46 min, 97.5% (Method B) 293

5-hydroxy-N-(3-(4-(neopentyloxy) phenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4- carboxamide 402.2/2.28 min (Method B) RT= 11.2 min, 87.8% (Method A) RT = 10.11 min, 100% (Method B) 294

5-hydroxy-N-(3-(4- isopropoxyphenyl)cyclopentyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4 carboxamide 374.2/2.01 min (MethodB) RT = 8.97 min, 92.6% (Method A) RT = 8.68 min, 93.9% (Method B) 295

N-((1R,3R)-3-(1-benzyl-1H-pyrazol- 4-ylcarbamoyl)cyclopentyl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 439.1/1.53min (Method B) RT = 6.08 min, 90.6% (Method A) RT = 6.09 min, 94.6%(Method B) 296

N-((1R,3R)-3-(benzo[d]thiazol-2- ylmethylcarbamoyl)cyclopentyl)-5-hydroxy-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxamide 430/1.51min (Method B) RT = 5.77 min, 93.9% (Method A) RT = 5.77 min, 91.8%(Method B) 297

5-hydroxy-2,6-dioxo-N-((1R,3R)-3- ((1s,4S)-4- phenylcyclohexylcarbamoyl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide 441.1/1.87 min(Method B) RT = 7.87 min, 98.6% (Method A) RT = 7.75 min, 89.8% (MethodB) 298

5-hydroxy-2,6-dioxo-N-((1R,3R)-3- ((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)cyclopentyl)-1,2,3,6- tetrahydropyrimidine-4-carboxamide413.1/1.76 min (Method B) RT = 6.92 min, 89.9% (Method A) R= 6.90 min,97.8% (Method B)

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from the groupconsisting of:

wherein each moiety is substituted with 0-2 R⁵; X₁ is independentlyselected from the group consisting of: a bond, O, CO, straight orbranched C₁₋₃ alkylene, —O—C₁₋₃ alkylene-, —C₁₋₃ alkylene-O—, NH, —SO₂—,—C₁₋₃ alkylene-NH—, —NHCO—, —CONH—, —CH₂NHCO—, —CH₂CONH—, —OCONH—,—CH₂OCONH—, —NHCONH—, and —SO₂NH—; alternatively,

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(CH₂)₂OH, —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₁₋₃Ph, 3-halo-4-halo-phenyl, 3-halo-5-CF₃-phenyl, and

R² is independently selected from the group consisting of: OH and NHR⁷;R⁴ is independently selected from the group consisting of: H, C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and a ringmoiety substituted with 0-2 R^(h) and selected from: C₃₋₁₀ carbocycleand a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S(O)_(p); R⁵ is,independently at each occurrence, selected from the group consisting of:halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NO₂, CO₂(C₁₋₄ alkyl), —CH₂CO₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), andN(C₁₋₄ alkyl)₂; R⁶ is independently selected from the group consistingof: H and C₁₋₄ alkyl substitute with 0-1 CO₂H, R⁷ is independentlyselected from the group consisting of: H, C₁₋₆ haloalkyl, COCF₃,—(CH₂)₂O(C₁₋₄ alkyl), C₁₋₆ alkyl substituted with 0-1 OH,—(CHR^(f))_(n)—(C₃₋₆ cycloalkyl substituted with 0-1 OH),—(CHR^(f))_(n)-(phenyl substituted with 0-2 R^(b)), 1-tetralinyl,1-indanyl, tetrahydronaphthalenyl, 1-Bn-pyrrolidin-3-yl,—(CH₂)_(n)-(piperidin-1-yl), 1-C₁₋₄ alkyl-piperidiny-4-yl, 1-CO₂(C₁₋₄alkyl)-piperidiny-4-yl, 1-(4-halo-phenyl)-piperidiny-4-yl,—(CH₂)_(n)(morpholin-4-yl), —(CH₂)_(n)-imidazolyl, —(CH₂)_(n)-pyridyl,

R⁸ is independently selected from the group consisting of: CO₂H and OH;R^(a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, NH₂, NO₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, CO₂H,CO₂(C₁₋₄ alkyl), NHCO(C₁₋₄ alkyl substituted with 0-1 NH₂), N(C₁₋₄alkyl)CO(C₁₋₄ alkyl), NHCO₂(C₁₋₄ alkyl), CONHSO₂(C₁₋₄ alkyl), SO₂(C₁₋₄alkyl), CONH₂, CONH(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), N(C₁₋₄alkyl)SO₂(C₁₋₄ alkyl), phenoxy, and —CONH(phenylcyclohexyl); R^(b) is,independently at each occurrence, selected from the group consisting of:halogen, OH, C₁₋₄ alkyl substituted with 0-1 OH, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, NH₂, NO₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄alkyl)₂, NHCO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and SO₂NH₂; R^(c) is,independently at each occurrence, selected from the group consisting of:═O and R^(b); R^(d) is, independently at each occurrence, selected fromthe group consisting of: CONH₂, C₁₋₄ alkyl, —(CH₂)₂O(CH₂)₂O(C₁₋₄ alkyl),C₃₋₆ carbocycle substituted with 0-2 R^(h), morpholin-1-yl, 1-C₁₋₄alkyl-piperazin-4-yl, 1-CBz-piperazin-4-yl, pyridyl, indol-3-yl, andbenzothiazol-2-yl; R^(e) is, independently at each occurrence, selectedfrom the group consisting of: H, C₁₋₄ alkyl, CO(C₁₋₄ alkyl), CO₂(C₁₋₄alkyl), CO₂(benzyl), CONH(C₁₋₄ alkyl), CONH(phenyl substituted with 0-2halogens), SO₂(C₁₋₄ alkyl), and —(CH₂)_(n)R^(d); R^(f) is, independentlyat each occurrence, selected from the group consisting of: H and methyl;R^(g) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, CO₂(C₁₋₄ alkyl), C₃₋₆ cycloalkyl, and phenyl; R^(h) is,independently at each occurrence, selected from the group consisting of:H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,—(CH₂)₂O(C₁₋₄ alkyl), CF₃, NO₂, CONH₂, OBn, quinolinyl, 1-C₁₋₄alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))pyrazolyl, 1-C₁₋₄alkyl-3-CF₃-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, N(C₁₋₄alkyl)₂, CONH₂, and NHCO(C₁₋₄ alkyl)); and n is, independently at eachoccurrence, selected from 0, 1, 2, and
 3. 2. A compound according toclaim 1, wherein: ring A is independently selected from the groupconsisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, —SO₂—, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CONH—,—CH₂NHCO—, —CH₂CONH—, —OCONH—, —CH₂OCONH—, —NHCONH—, and —SO₂NH—;alternatively,

R¹ is independently selected from the group consisting of: H, C₁₋₄alkyl, —(CH₂)₂OH, —CH₂CO₂H, CH₂CF₃, CH₂CH₂CF₃, —(CH₂)₁₋₃Ph, and

R³ is independently selected from the group consisting of: H, C₁₋₄alkyl, CH₂CF₃, —(CH₂)₁₋₃Ph, 3-halo-4-halo-phenyl, 3-halo-5-CF₃-phenyl,and benzyl; R⁴ is independently selected from the group consisting of:H, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, pyrazolyl,oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, benzothiazolyl, and1H-pyrazolo[3,4-d]pyrimidinyl; R⁵ is, independently at each occurrence,selected from the group consisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,CO₂(C₁₋₄ alkyl), and NH₂; R⁷ is independently selected from the groupconsisting of: H, C₁₋₆ alkyl substituted with 0-1 OH, C₁₋₆ haloalkyl,—(CH₂)₂O(C₁₋₄ alkyl), C₃₋₆ cycloalkyl, —CH(CH₃)(cyclohexyl),—(CH₂)₁₋₃-(phenyl substituted with 0-2 R^(b)), tetrahydronaphthalenyl,1-Bn-pyrrolidin-3-yl, 1-C₁₋₄ alkyl-piperidin-4-yl,—(CH₂)₂(piperidin-1-yl), —(CH₂)₂(morpholin-4-yl),—(CH₂)₃(morpholin-4-yl), —(CH₂)₂(1H-imidazo 4-yl),—(CH₂)₃(imidazol-1-yl), —CH₂-pyridyl, and

and R^(h) is, independently at each occurrence, selected from the groupconsisting of: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —(CH₂)₂O(C₁₋₄alkyl), CF₃, NO₂, CONH₂, OBn, quinolinyl, 1-C₁₋₄ alkyl-pyrazolyl,1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-C₁₋₄ alkyl-3-CF₃-pyrazolyl,1-Ph-5-C₁₋₄ alkyl-pyrazolyl, 1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazolyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, N(C₁₋₄ alkyl)₂, CONH₂, andNHCO(C₁₋₄ alkyl)).
 3. A compound according to claim 2, wherein thecompound is of Formula (II):

or as stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.
 4. A compound according to claim 3, wherein: ring A isindependently selected from the group consisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, SO₂, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CH₂NHCO—,—CH₂CONH—, —CH₂OCONH—, and —SO₂NH—; alternatively,

R¹ and R³ are each independently selected from the group consisting of:H, C₁₋₄ alkyl, CH₂CF₃, and benzyl; R⁴ is independently selected from thegroup consisting of: H, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, pyrazolyl,oxadiazolyl, triazolyl, pyridyl, benzothiazolyl, and1H-pyrazolo[3,4-d]pyrimidinyl; R⁵ is, independently at each occurrence,selected from the group consisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,and CO₂(C₁₋₄ alkyl); R⁷ is independently selected from the groupconsisting of: H, C₁₋₆ alkyl, CH₂CF₃, —(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)₂OH,—CH(CH₃)CH₂OH, —CH₂C(CH₃)₂OH, C₃₋₆ cycloalkyl, —CH(CH₃)(cyclohexyl),—(CH₂)₁₋₃-(phenyl substituted with 0-2 R^(b)), tetrahydronaphthalenyl,1-Bn-pyrrolidin-3-yl, 1-C₁₋₄ alkyl-piperidin-4-yl,—(CH₂)₂(piperidin-1-yl), —(CH₂)₂(morpholin-4-yl),—(CH₂)₃(morpholin-4-yl), —(CH₂)₂(1H-imidazol-4-yl),—(CH₂)₃(imidazol-1-yl), —CH₂(pyrid-3-yl), —CH₂(pyrid-4-yl), and

R^(b) is, independently at each occurrence, selected from the groupconsisting of: halogen, CH₂OH, CF₃, and SO₂NH₂; R^(d) is, independentlyat each occurrence, selected from the group consisting of: C₁₋₄ alkyland phenyl substituted with 0-2 R^(h); and R^(h) is, independently ateach occurrence, selected from the group consisting of: H, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CONH₂, OBn, quinolinyl, 1-C₁₋₄alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-C₁₋₄alkyl-3-CF₃-pyrazolyl, 1-Ph-5-C₁₋₄ alkyl-pyrazolyl,1-((CH₂)₂(morpholin-4-yl))-pyrazolyl,1-(tetrahydro-2H-pyran-2-yl)-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,2-Ph-4-C₁₋₄ alkyl-thiazoyl, —NHSO₂(phenyl substituted with C₁₋₄ alkyl),and —(CH₂)₀₋₂-(phenyl substituted with zero to three substituentsindependently selected from the group consisting of: halogen, CH₂OH,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, N(C₁₋₄ alkyl)₂, CONH₂, andNHCO(C₁₋₄ alkyl)).
 5. A compound according to claim 4, wherein: ring Ais independently selected from the group consisting of:

X₁ is independently selected from the group consisting of: a bond, O,CH₂, CO, SO₂, —CH₂CH₂—, —CH₂O—, —OCH₂—, NH, —CH₂NH—, —NHCO—, —CONH—,—CH₂OCONH—, and —SO₂NH—; R⁴ is independently selected from the groupconsisting of: H, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, CF₃,

and a ring moiety substituted with 0-2 R^(h) and selected from: C₃₋₆cycloalkyl, phenyl, tetrahydronaphthalenyl, pyrazolyl, oxadiazolyl,triazolyl, pyridyl, benzothiazolyl, and 1H-pyrazolo[3,4-d]pyrimidinyl;R⁷ is independently selected from the group consisting of: H,—(CH₂)₂O(C₁₋₄ alkyl), —CH₂C(CH₃)₂OH, cyclopentyl, 4-halo-benzyl,2-CH₂OH-benzyl, 3-CF₃-benzyl, 2-halo-phenethyl, 4-halo-phenethyl,—(CH₂)₃Ph, 1-Bn-pyrrolidin-3-yl, —(CH₂)₂(piperidin-1-yl),—(CH₂)₂(morpholin-4-yl), —(CH₂)₃(morpholin-4-yl),(CH₂)₂(1H-imidazol-4-yl), and —CH₂(pyrid-3-yl); and R^(h) is,independently at each occurrence, selected from the group consisting of:H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OBn, quinolinyl, 1-C₁₋₄alkyl-pyrazolyl, 1-(CH₂CO₂(C₁₋₄ alkyl))-pyrazolyl, 1-Ph-pyrazolyl,1-C₁₋₄ alkyl-3-CF₃-pyrazolyl, 1-Ph-5-C₁₋₄ alkyl-pyrazolyl,1-((CH₂)₂(morpholin-4-yl))-pyrazolyl, 1,2,5-triC₁₋₄ alkyl-pyrazolyl,—NHSO₂(phenyl substituted with C₁₋₄ alkyl), and —(CH₂)₀₋₁-(phenylsubstituted with zero to three substituents independently selected fromthe group consisting of: halogen, CH₂OH, CONH₂, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, and N(C₁₋₄ alkyl)₂).
 6. A compound according toclaim 5, wherein: R¹ and R³ are each independently selected from thegroup consisting of: H, C₁₋₄ alkyl and benzyl;

is independently selected from the group consisting of:

and R⁷ is independently selected from the group consisting of: H,—(CH₂)₂O(C₁₋₄ alkyl), —CH₂C(CH₃)₂OH, 4-halo-benzyl, 4-halo-phenethyl,—(CH₂)₂(morpholin-4-yl), and —(CH₂)₃(morpholin-4-yl).
 7. A compoundaccording to claim 2, wherein the compound is of Formula (III):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 7, wherein: R¹ isindependently selected from the group consisting of: H, C₁₋₄ alkyl,—(CH₂)₂OH, —CH₂CO₂H, CH₂CF₃, CH₂CH₂CF₃, —(CH₂)₁₋₃-Ph,

R³ is independently selected from the group consisting of: H, C₁₋₄ alkyland benzyl and

is independently selected from the group consisting of:


9. A compound according to claim 1, wherein the compound is selectedfrom the following:

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.
 10. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a compound of claim 1, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.